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Effects of grapefruit juice on the pharmacokinetics of sildenafil

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Abstract

Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods. Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.

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... These conditions mimic the intragastric parameters before and after bariatric surgery, including pH, fluid volume, temperature, and gastric contractility. Samples of 300 µL were drawn at 5,10,15,20,30,40,50,60,75, and 90 min, filtered, and centrifuged for 12 min at 20,817× g (37 • C) before UPLC analysis. ...
... However, the degree of nonproportionality for doses up to 200 mg is considered small and not clinically significant [49,51]. Moreover, sildenafil exhibits pronounced interindividual pharmacokinetic variability [50] implying that a two-fold prediction error is acceptable for this compound. ...
... However, the degree of nonproportionality for doses up to 200 mg is considered small and not clinically significant [49,51]. Moreover, sildenafil exhibits pronounced interindividual pharmacokinetic variability [50] implying that a two-fold prediction error is acceptable for this compound. 3 and AUC in Supplementary Table S2) does not seem to be affected by the altered GI conditions after bariatric surgery. ...
Article
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Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.
... How-ever, co-administration of sitaxentan (endothelin receptor antagonist) with sildenafil has been reported to clinically insignificant (Stavros et al., 2010). Clinical research on strong inhibitors of cytochrome P450, specifically, coadministration of sildenafil with potent 3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, and protease inhibitors, suggest caution with dosing (Krenzelok, 2000;Corbin and Francis, 2002;Jetter et al., 2002). Even inhibitors of 3A4 that exist in grapefruit juice have been shown to alter sildenafil biometabolism. ...
... This result urged physicians to practice cautioning of patients who are experimenting with such a combination (Jetter et al., 2002). Strong inhibitors of 3A4 can overburden and inhibit the enzyme, resulting in elevated sildenafil serum concentration (Muirhead et al., 2000;Corbin and Francis, 2002) and could enhance pharmacological and toxicological effects (Corbin and Francis, 2002). ...
... It is suggested that administration of sildenafil with inhibitors of 3A4 should consider using a lower starting dose (Krenzelok, 2000;Corbin and Francis, 2002;Jetter et al., 2002) and yet others suggest that those on 3A4 inhibitors should not exceed the usual minimum dosage of 25 mg in any 48 h period (Krenzelok, 2000). Dosage of sildenafil with 3A4 inhibitors has demanded some extent of caution. ...
Article
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Novel drugs for Erectile Dysfunction (ED) must be assessed for their interactions with other already approved medications that are processed through similar metabolic pathways. The cytochrome P450 enzyme family, in particular 3A4 isoform, is ubiquitously used to oxidize azole antifungals, erythromycin, and HIV protease inhibitors. Administering multiple medications using cytochrome P450 CYP3A4 (3A4) as a primary metabolic route may cause unexpected toxicological effects in patients. Current U.S Food and Drug Administration (FDA) approved ED drugs such as sildenafil (Viagra), tadalafil (Levitra), and vardenafil (Cialis), all Phosphodiesterase-5 inhibitors, are also metabolized by 3A4. The overlapping metabolic pathways for the above mentioned PDE-5 inhibitors are known, however it is still imperative to discover any negative clinical manifestations that may arise from their concomitant use or their use with other substrates that are metabolized by 3A4 enzyme. Worldwide, approximately 150 million men are struggling with ED, making this research a valid obligation. Consequently, interaction of the widely prescribed ED drugs and their interactions with 3A4 enzyme are discussed in this review.
... In particular, Group T showed an increased T1/2 compared to Group N (p < 0.005) and the CL/F value of Group T was significantly lower than that of Group N (p < 0.005). These results showed that the inhibition of hepatic CYP3A metabolism and the reduction of the first pass effect increased the exposure of tadalafil [39]. Table 1. ...
... In particular, Group T showed an increased T 1/2 compared to Group N (p < 0.005) and the CL/F value of Group T was significantly lower than that of Group N (p < 0.005). These results showed that the inhibition of hepatic CYP3A metabolism and the reduction of the first pass effect increased the exposure of tadalafil [39]. ...
Article
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Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.
... However, the outcome of these interactions has been inconsistently reported. For example, grapefruit juice increases the bioavailability and area under the concentration-time curve (AUC) of sildenafil by 23 % without affecting its maximum plasma concentration (C max ) [4]. Additionally, co-administration of ciprofloxacin and clarithromycin significantly increases sildenafil bioavailability [5]. ...
... At least a 1-week washout period was required between each intervention ( Fig. 1). A 1-week washout period is sufficient for complete elimination of sildenafil [4]. ...
Article
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PurposeSeveral severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose. Methods We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration. ResultsCompared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study. Conclusions Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.
... Clinical research on strong inhibitors of cytochrome P450, specically, co-administration of Sildenal with potent 3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, and protease inhibitors, recommend carefulness with dosing [20,23]. Even inhibitors of CYP3A4 that exist in grapefruit juice have been shown to alter Sildenal bio-metabolism [24]. ...
... Grapefruit juice significantly enhanced the increase in the exposure (measured as the area under the curve or AUC) of sildenafil in the body from 620 to 761 ng/mL per hour. Additionally, it caused a delay in the time it took for the maximum concentration of sildenafil (T max ) to be reached from 0.75 to 1.13 h [110]. The absorption of drugs such as celiprolol, acebutolol, talinolol, and fexofenadine is known to be affected by grapefruit juice [111]. ...
... Grapefruit juice has been found to increase the bioavailability of sildenafil and to delay its absorption. This might be due to a delay in gastric emptying or an alteration in gastric pH value (Jetter et al., 2002). Green tea decreased the plasma concentration of nadolol probably due to inhibition of OATP1A2-mediated intestinal absorption (Misaka et al., 2014) and milk reduces the absorption of levothyroxine likely due to an interference of calcium with the drug absorption (Chon et al., 2018). ...
Article
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Older adults are the main users of medicine and due to their multimorbidity are often faced/confronted with a complex medication management. This review article provides a brief overview on aspects of medication management such as maintaining a stock of the required medicine, understanding and following the instructions for use, coping with the primary and secondary packaging as well as preparation prior to use. The main focus however is on the drug intake itself and provides an overview about the current understanding of real life dosing conditions of older adults and geriatric patients. Furthermore, it elaborates the acceptability of dosage forms, in particular solid oral dosage forms as they represent the majority of dosage forms taken by these patient populations. An improved understanding of the needs of older adults and geriatric patients, their acceptability of various dosage forms and the circumstances under which they manage their medications, will make the design of more patient-centric drug products possible.
... In a review by Bailey DG et al. grapefruit juice used together with sildenafil caused serious systemic vasodilatation especially in combination with a nitrate. Moreover, consumption of grapefruit juice together with sildenafil caused small increases in the mean oral bioavailability of the drug (Bailey and Dresser 2004).Another study indicated that grapefruit juice increased the bioavailability of this drug, leading to unpredictable pharmacokinetics(Jetter 2002). Grape juice was also seen to increase sildenafil's bioavailability (Amadi and Mgbahurike 2018). ...
Article
The use of medicines is associated with both therapeutic and adverse effects and interactions. In particular, interactions between drugs and food are common, and can either enhance the action of drugs or diminish their effect. Health professionals have a responsibility to screen for and educate patients about food–drug interactions, as well as to assist in decreasing their occurrence. The aim of this study was to identify any interactions present between food and selected over-the-counter (OTC) drugs. Sixty-five publications out of a potential 1112 found in the search were included in the study and among them 28 concerned painkillers, 6 – antihistamines, 4 – nasal decongestants, 10 were for proton pump inhibitors and for iron and 8 for sildenafil. Interactions between food and OTC drugs do exist. These drugs should not be taken regardless of the meal. Providing relevant information to the patient will increase drug safety and efficacy.
... sildenafil and N-desmethyl sildenafil was remained unaffected by grapefruit juice (Jetter et al., 2002). s0070 11.4.1.2 ...
Chapter
Simultaneous administration of food and the drugs can cause significant changes in the drug bioavailability than the fasted state. Changes in bioavailability due to food–drug interactions (FDIs) can substantially influence drug development, clinical settings, and regulatory decisions. This chapter describes the regulatory consideration to perform FDIs, the influence of gastrointestinal physiological factors on drug pharmacokinetics (PK), and a focused discussion on the specific FDIs was accomplished. Furthermore, formulations approach to mitigate the FDIs were also discussed briefly in the last section. This chapter comprehensively discusses FDIs, regulatory aspects of FDIs, consequences of administered food on orally ingested drugs PK parameters, some of the most prominent food interactions with drugs, and finally, formulation approaches to minimize the negative FDIs.
... The bioavailability of SILD was increased in a randomized crossover study in which male volunteers received a single 50 mg dose of SILD when co-administered with Grapefruit juice. Although patients are unlikely to be harmed if they take Grapefruit juice at the same time, it is prudent to avoid this combination 36 . ...
... Although an approximate 30% increase in t 1/2 (3.48 vs. 2.66 h) was observed, an unexpected similarity in AUC 0-24 and delay in T max by about 69% was found when compared with our population (Table 1 and 2). In another study of 24 healthy Caucasian males who received a 50-mg single oral dose of sildenafil citrate, Jetter et al. found a relatively lower C max than reported in the previous two studies (Table 2), which was reached early with a T max of 0.75 h (Jetter et al., 2002). A comprehensive comparison of the weighted mean plasma concentration-time curves of 100 mg sildenafil citrate after digitization between Middle Eastern, Mexican, and Caucasians is depicted in Fig. 4. ...
Article
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Aim 1) To investigate the pharmacokinetic profile of sildenafil citrate in Middle Eastern males and, 2) To highlight the impact of ethnicity on its pharmacokinetics parameters through comparing Middle Eastern data to the data estimated from different ethnic groups. Method The study was conducted on 24 Middle Eastern healthy male volunteers. Pharmacokinetic data including Cmax, Tmax, t1/2, AUC0-t, AUC0-∞ were estimated from blood samples collected at several time points within 24 hours post-administration of a single 100-mg tablet of sildenafil citrate (Viagra®). Pharmacokinetic data of sildenafil generic 100-mg tablet (product B) was determined in the volunteers using the same analytical method. Pharmacokinetic data of other studies published on different ethnicities were obtained and compared to our Viagra®-related data. Results Analysis of Middle Eastern data (mean ± SD) revealed Cmax = 398.9 ± 107.7 ng/ml; Tmax = 1.84 ± 0.22 hours; t1/2 = 2.66 ± 0.97 h; AUC0–24 = 1475 ± 515.3 ng.h/ml; AUC0-∞ = 1556 ± 567.58 ng.h/ml. There was no significant difference between Viagra® and product B, confirming the bioequivalence of the two preparation as well as the reliability of utilized analytical method. Data comparisons between Middle Eastern and other ethnicities indicated that Iranian, Mexican, and Thai would potentially have twice the effect observed in Arabs and Caucasians, considering the same prescribed drug formulation and dose. Conclusion There is a considerable difference in the pharmacokinetic profile of sildenafil citrate between Middle Eastern and other ethnic groups. Ethnicity may predispose individuals to unwanted prolonged activity of sildenafil and adverse events. Thus, it should be taken in consideration by clinicians when recommending sildenafil dose.
... Clinical research on strong inhibitors of cytochrome P450, specically, co-administration of Sildenal with potent 3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, and protease inhibitors, recommend carefulness with dosing [20,23]. Even inhibitors of CYP3A4 that exist in grapefruit juice have been shown to alter Sildenal bio-metabolism [24]. ...
Article
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OBJECTIVE: Sildenal is majorly metabolized by Cytochrome P450 (CYP450) isoform 3A4. The latter is responsible for the metabolism of more than 50% of the drugs. It is involved in multiple clinically relevant drug-drug interactions. To evaluate the mice pharmacokinetics model as a drug- drug interaction model by using Sildenal in the presence of Carbamazepine (CYP3A4 inducer) and Ketoconazole (CYP3A4 inhibitor) in male Swiss albino mice. Also, efforts have been put-forth to employ cannulated mice and compare the data with the non-cannulated mice. METHODOLOGY: Ketoconazole and Carbamazepine (10 mg/kg, PO) were dosed for 6 days in different groups of mice. On day 6 Sildenal (10 mg/kg, PO) was dosed 15 minutes post Ketoconazole and Carbamazepine administration. Two control groups were dosed with Sildenal alone. Blood samples were collected through retro-orbital plexus for sparse sampling and jugular vein for cannulated mice at 0.25, 0.5, 1, 2, 4 and 8 h post Sildenal administration and analyzed by LC-MS/MS. RESULTS: Ketoconazole increased the C and AUC of Sildenal by 146% and 219% in non-cannulated and 63% and 194% in cannulated max last mice respectively, as compared to control group. Carbamazepine decreased the C and AUC of Sildenal by 36% in non-cannulated mice and 61% and 58% in cannulated mice respectively, as max last compared to control group. There was no signicant difference in the pharmacokinetic parameters of Sildenal in cannulated and noncannulated groups. The study reects to the underlying drug-drug interactions which can attribute in the pharmacokinetics of Sildenal, in the presence of drugs, which are inducers and inhibitors of CYP3A4. Also, that cannulated mice can be employed to reduce the animal usage by one third without compromising the data quality.
... The bioavailability of SILD was increased in a randomized crossover study in which male volunteers received a single 50 mg dose of SILD when co-administered with Grapefruit juice. Although patients are unlikely to be harmed if they take Grapefruit juice at the same time, it is prudent to avoid this combination 36 . ...
Article
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Erectile dysfunction (ED) is defined as a man's inability to achieve or maintain an erection long enough to complete sexual activity. Sildenafil (SILD) is a drug that is used to treat ED all over the world. In this review article, the interactions between SILD and herbal supplements recorded in the literature were summarized using the Medline database (via PubMed) and the key-words: Sildenafil, herbal supplements, and interactions. In the present review article, pharmacokinetic (PK) and pharmacodynamic (PD) interactions were reported during co-administration of herbal supplements with SILD. Reduction in SILD bioavailability was found as a result of interaction of SILD with Horny goat weed, Thai ginseng, Arugula, Black seed, Garden cress, Fenugreek, and Pummelo juice in human and/or animal models. Meanwhile, Citrus lemon juice has not significantly altered the PK of SILD. Also, PD interactions were found as a result of the interaction of Curcumin, Yohimbine, and Pomegranate juice in human and rat models. Healthcare professionals should be aware of this potential and researchers should strive to fill the numerous gaps in our present understanding of this problem.
... A study of the effect of grapefruit juice on the pharmacokinetics of sildenafil found that grapefruit juice increased the AUC0-inf of sildenafil by 23% and the Tmax period was delayed by 0.25 h, suggesting that grapefruit juice enhances the rate and extent of the absorption of sildenafil; therefore, it is not advisable to consume grapefruit juice alongside sildenafil treatment [10]. ...
Article
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Sildenafil citrate, a widely-used oral therapy for erectile dysfunction, is a cytochrome P3A4 (CYP3A4) enzyme substrate. Studies have reported that this substrate has an inhibitory effect on CYP3A4 enzymes in long-term cigarette and cannabis smokers, which predominantly mediate the hepatic elimination of sildenafil. Cigarette and/or cannabis smoking could therefore alter the exposure of sildenafil. The aim of this study was to examine the effect of smoking cigarettes and/or cannabis on the pharmacokinetics, pharmacodynamics, safety and tolerability of sildenafil. Thirty-six healthy human subjects were equally divided into three groups: non-smokers, cigarette smokers and cannabis smokers. Each group was administered a single dose of sildenafil (50 mg tablets). The primary outcome measures included the maximum concentration of sildenafil in plasma (Cmax), the elimination half-life (t1/2) and the area under the plasma concentration time curve from zero to time (AUC0–t). The pharmacodynamics were assessed by the International Index of Erectile Function (IIEF-5). The exposure of sildenafil (AUC0–t) showed a statistically significant increase in cigarette smokers (1156 ± 542 ng·h/mL) of 61% (p < 0.05) while in cannabis smokers (967 ± 262 ng·h/mL), a non-significant increase in AUC0–t of 35% (p > 0.05) was observed relative to non-smokers (717 ± 311 ng·h/mL). Moreover, the Cmax of sildenafil increased by 63% (p < 0.05) and 22% (p > 0.05) in cigarette smokers and cannabis smokers, respectively. Cigarette smoking increases the exposure of sildenafil to a statistically significant level with no effect on its pharmacodynamics, safety and tolerability.
... Except from drugs, substances that may affect the first-pass metabolism controlled by CYP3A4 such as grapefruit, which claim a significant inhibitory effect, could also alter the pharmacokinetics of sildenafil. A relevant clinical study conducted on healthy male volunteers exposed that intake of 50 mg sildenafil with grapefruit juice influenced its oral bioavailability causing a 23% increase due to the reduction of its first-pass metabolism and consequent delay in absorption [83]. Surprisingly, the opposite effect on bioavailability was observed when sildenafil was co-administered with pummelo juice. ...
Article
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Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.
... In a review by Bailey DG et al. grapefruit juice used together with sildenafil caused serious systemic vasodilatation especially in combination with a nitrate. Moreover, consumption of grapefruit juice together with sildenafil caused small increases in the mean oral bioavailability of the drug (Bailey and Dresser 2004).Another study indicated that grapefruit juice increased the bioavailability of this drug, leading to unpredictable pharmacokinetics(Jetter 2002). Grape juice was also seen to increase sildenafil's bioavailability (Amadi and Mgbahurike 2018). ...
... This suggests that lower sildenafil doses are required for patients receiving such drugs. [8][9][10][11] Ciprofloxacin and clarithromycin are known inhibitors of CYP3A4, which have been reported to produce clinically significant interactions with a number of other therapeutic agents that are substrates for this isoenzyme. [12][13][14][15] Because of the widespread use of sildenafil and since ciprofloxacin and clarithromycin are widely used antibiotics, it is very likely that some patients may use these drugs simultaneously. ...
... antihistamine, anthelmintic, and anti-inflammatory drugs [10][11][12][13][14][15][16][17][18][19] . The intervention of GFJ and naringin in such processes has been found in various in vitro and in vivo assays, as well as in computational modeling studies. ...
Article
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Grapefruit juice (GFJ) and naringin when consumed previously or together with medications may alter their bioavailavility and consequently the clinical effect. Ifosfamide (IF) is an antitumoral agent prescribed against various types of cancer. Nevertheless, there is no information regarding its interaction with the ingestion of GFJ or naringin. The aims of the present report were validating a method for the quantitation of IF in the plasma of mouse, and determine if mice pretreated with GFJ or naringin may modify the IF pharmacokinetics. Our HPLC results to quantify IF showed adequate intra and inter-day precision (RSD < 15%) and accuracy (RE < 15%) indicating reliability. Also, the administration of GFJ or naringin increased Cmax of IF 22.9% and 17.8%, respectively, and decreased Tmax of IF 19.2 and 53.8%, respectively. The concentration of IF was higher when GFJ (71.35 ± 3.5 µg/mL) was administered with respect to that obtained in the combination naringin with IF (64.12 ± µg/mL); however, the time required to reach such concentration was significantly lower when naringin was administered (p < 0.5). We concluded that pre-administering GFJ and naringin to mice increased the Tmax and decreased the Cmax of IF.
... In a review by Bailey DG et al. grapefruit juice used together with sildenafil caused serious systemic vasodilatation especially in combination with a nitrate. Moreover, consumption of grapefruit juice together with sildenafil caused small increases in the mean oral bioavailability of the drug (Bailey and Dresser 2004).Another study indicated that grapefruit juice increased the bioavailability of this drug, leading to unpredictable pharmacokinetics(Jetter 2002). Grape juice was also seen to increase sildenafil's bioavailability (Amadi and Mgbahurike 2018). ...
... Several papers reported that Sildenafil pharmacokinetics are altered in response to food-drug (or drug-drug) interactions 5,[15][16][17] . It has been demonstrated the co-administration of sildenafil with potent CYP3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, and protease inhibitors causes a significant increase in plasma sildenafil levels 18,19 . Another example of interaction is Sitaxentan (endothelin receptor antagonist), which when administered with sildenafil, demonstrated a weak, but a statistically significant interaction 20 . ...
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Both sildenafil and RED BULL®(energy drink) are claimed to boost up energy.RED BULL®, one of the most commonly used energy drinks and its easily and widely available for daily use, the idea of this research work had arisen from observations about the concomitant use of sildenafil with RED BULL® by men seeking for better sexual performance. To study the effect of RED BULL® on the pharmacokinetic profile of sildenafil by using HPLC. The pharmacokinetic parameters (Cmax, Tmax and AUC) were determined in 10 rats following oral administration of 0.57 mg/ml sildenafil with and without RED BULL® in crossover design, to achieve this purpose,simple, rapid and accurate method for validation and determination of sildenafil in rat plasma in the presence of RED BULL® has been developed. This was performed using High-Performance Liquid Chromatography- Ultra Violet (HPLC-UV). The pharmacokinetic data showed that sildenafil plasma level was lower when combined with RED BULL® According to the results obtained, maximum concentration (Cmax) for sildenafil alone was (162.05 ng/ ml) after 0.5 hours of administration. The Cmax decreased to (44.68 ng/ml) after 0.5 hoursof administration RED BULL® concomitantly with sildenafil which showed a significant effect on sildenafil plasma level (P<0.001). The area under the curve (AUC) decreased significantly from (370.53 ng/ml∗hr) for sildenafil alone to (87.74 ng/ml∗hr) when combined with RED BULL®. RED BULL® can alter sildenafil pharmacokinetic if they were taken together.
... GT catechins have inhibitory effect not only on CYP3A and CYP2C8, as described above, but also on CYP2C9 in vitro [14,15]. Previous studies demonstrated that grapefruit juice slightly increased sildenafil exposure possibly by inhibiting intestinal CYP3A [31]. Therefore, GT-sildenafil interaction might be explained by an inhibition of CYP3Amediated sildenafil metabolism (Table 1). ...
Article
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Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, available data on GT interaction with CV compounds with a narrow therapeutic index, such as warfarin and tacrolimus, derive from single case reports. Conversely, GT interactions with simvastatin, rosuvastatin, nadolol and sildenafil were documented through pharmacokinetic studies. In these, the effect of GT or GT derivatives on drug exposure was mild to moderate, but a high inter-individual variability was observed. Further investigations, including studies on the effect of the dose and the time of GT intake are necessary to understand more in depth the clinical relevance of GT-CV drug interactions.
... Furthermore, it is advisable to avoid taking the drug along with fatty food, as it may alleviate its effect. In addition, it is inadvisable to wash the drug down with grapefruit juice (other kinds of fruit juice are not recommended as well), since it blocks the CYP3A4 enzyme responsible for the metabolism of PDE-5 inhibitors, which may intensify their side-effects in the same way as alcohol does [36,37]. ...
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An increasing number of men around the world suffer from erectile dysfunction (ED). Indeed, according to the sexuality study conducted by Professor Izdebski, 1 out of 10 men in Poland suffers from ED. The problem is found among men of any age, however, 60% of all patients are between 40 and 60 years old, thus in their prime, and who still want to fully enjoy life. Not only do the effects of ED affect a man, but they have influence on his relationship and partner as well. In spite of a growing awareness within society, the problem remains perceived as embarrassing, which leads patients to treat themselves on their own, delaying a visit to their doctors. Meanwhile, in many cases, ED may be the first symptom of more serious diseases, such as diabetes, or result from the sideeffects of applied drugs. A breakthrough in the oral medication treatment of ED was observed when a new phosphodiesterase type 5 inhibitor (PDE-5-inhibitor) - sildenafil citrate (Viagra®) - was introduced. Nowadays, 5 active substances from this group are being applied. The current medical guidelines recommend PDE-5 inhibitors as the firstline therapy for most men with ED, irrespective of the cause and severity of the disease. Recently, sildenafil at the dose of 25 mg came into the market without prescription. This paper presents an overview and update of the PDE-5 inhibitors.
... Likewise included in this group are drugs such as felodipine, nicardipine, lacidipine, amlodipine, verapamil, nitrodipine, pranidipine, nimodipine, and nisoldipine (Kane and Lipsky, 2000). In addition to these, there are HMG-CoA reductase inhibitors, immunosuppressant agents, inhibitors of VIH protease, phosphodiesterase type 5 inhibitors, antihistamins, antihelmints, and anti-inflammatory agents (Benton et al., 1996;Ku et al., 1998;Kupferschmidt et al., 1998;Castro et al., 2002;Jetter et al., 2002;Mahgoub, 2002). ...
... In einer Studie mit gesunden Freiwilligen stieg die AUC jedoch nur um das 2,3-Fache [12]. Grapefruitsaft steigert die Sildenafil-Exposition durchschnittlich um 23 % mit einer Bandbreite vom 0,8-bis 2,6-Fachen des AUC-Werts im Vergleich zur Kontrollgruppe [1,13]. ...
Article
Für die Bewertung des pharmakokinetischen Interaktionspotenzials der Phosphodiesterase(PDE)-5-Hemmer ist die Affinität zum Cytochrom-P450(CYP)-Isoenzym 3A4 von maßgeblicher Bedeutung. In der Interaktionstabelle (Tab. 1) wird das Verhalten der Substanzen zu diesem Cytochrom-P450-Isoenzym dargestellt.
... Their presence in this organ has clinical consequences since the inhibition of intestinal enzymes by medications or food can very significantly increase the levels of the medications administered, e.g. calcium channel blockers (Geró nimo-Pardo et al., 2005) or sildenafil (Jetter et al., 2002). ...
Article
Human growth and development consist of a continuum of biological events. The impact of these developmental changes in drug disposition is largely related to changes in the body composition (e.g. body water content, plasma protein concentrations) and in the function of organs important in metabolism (e.g. the liver) and excretion (e.g. the kidney). The gastric emptying time during the neonatal period is prolonged, as well as intestinal motility. The ratio of body surface area to body weight is higher in children than in adults, which results in higher absorption of locally applied corticosteroids. Lower plasma protein levels and a higher body water content compared to adults may lead to diminished drug distribution. Phase I drug metabolizing system develops quickly and reaches adult levels between the third and sixth year of age. In newborns up to 3 months, the sulphotransferase activity is more developed than glucuronidation. Glomerular filtration, normalized to body surface area, approaches adult levels by 6 months of age. During the first decade of life, these changes are dynamic and can be non-linear and discordant, making standardized dosing inadequate. During rapid phases of growth/development, drug disposition and response may be altered. The main goal is to optimize drug therapy in children. This can be achieved through a fundamental understanding of how ontogeny influences pharmacokinetics.
... As would be expected, inhibitors of CYP3A4, including erythromycin (Muirhead et al., 2002a) and the protease inhibitors ritonavir and saquinavir increase the AUC and C max of sildenafil. Grapefruit juice, a further inhibitor of CYP3A4, increases the AUC but does not affect C max (Jetter et al., 2002). Coadministration of CYP2C9 inhibitors, including tolbutamide and warfarin, do not affect the pharmacokinetics of sildenafil . ...
Thesis
Nitric oxide is released from the endothelium and causes relaxation of vascular smooth muscle by stimulating guanylate cyclase to produce guanosine 3’,5’-cyclic monophosphate (cGMP) which, in turn, is degraded by phosphodiesterase type 5 (PDE5). Inhibition of PDE5, with drugs like sildenafil citrate, promotes NOstimulated relaxation of vascular smooth muscle. The overall aim of the work contained within this thesis was to further characterise the systemic vascular effects of PDE5 inhibition. Four clinical studies were performed. The aims of the first study were to investigate in healthy men the effect of smoking on endothelium-dependent vasomotor function measured as the change in peripheral arterial wave reflection with inhaled salbutamol, and the effect of acute sildenafil 100 mg on this response. Smokers (n=12) exhibited a reduced response to inhaled salbutamol compared to non-smokers (n=11) [mean(standard deviation) area under the curve of the change in central augmentation index following salbutamol 400 μg: -29(143) AU in smokers vs -159(124) AU in non-smokers, P=0.03]. In the smokers, there was a trend to an improvement in the response to salbutamol following sildenafil [-96(266) AU vs -29(143) AU with matched placebo; P=0.2]. The co-administration of glyceryl trinitrate (GTN) and sildenafil is absolutely contraindicated because of the potential for profound hypotension. The aim of the second study was to characterise the time course of this interaction. Twenty men with stable angina, maintained on their usual medicines, were administered sublingual GTN 400 μg 1, 4, 6 and 8 hours after sildenafil 100 mg or matched placebo. Compared to the combination of GTN and placebo, the combination of GTN and sildenafil resulted in greater mean maximum reductions from baseline in sitting systolic blood pressure (BP) at 1, 4 and 8 hours, and in sitting diastolic BP at all time points (all P
... However, using the GFJ method, the F g,GFJ values of tacrolimus and sildenafil were determined to be 0.48 and 0.81, respectively. 54,56 Considering the direction of the differences in F a and F g by the feces method and the GFJ method, different methods for the determination of F a and F g can explain the discrepancies observed in clinical situations. Another possible explanation for the discrepancies is that GFJ is assumed to inhibit intestinal CYP3A completely. ...
Article
Conventionally, it is believed that the fraction of orally administered drugs absorbed from the intestine (Fa) and intestinal availability (Fg) are independently determined by the apical membrane permeation and intestinal metabolism, respectively. However, the validity of this belief has not been well discussed, and Fa and Fg are often used without careful definition. In this review, Fa and Fg are mathematically described based on their definitions under the linear kinetics of metabolism and transport. Even considering with different models, intestinal metabolic enzymes such as cytochrome P450 3A affected both Fa and Fg, whereas apical efflux transporters including P-glycoprotein had no influence on Fg at least under the linear condition. To determine whether Fa and Fg calculated using different clinical methods are identical, empirical Fa and Fg were mathematically described based on “feces method” and “grapefruit juice method” and compared with their definitions. Fa and Fg obtained by the feces method corresponded with their definitions whereas the grapefruit juice method provided smaller Fa and larger Fg particularly for dual substrates of P-glycoprotein and cytochrome P450 3A with low membrane permeability. Our analyses suggest that the definitions and calculation methods of Fa and Fg should be considered when we intend to separately determine these values.
... Many studies prove that a huge portion of drugs is interacted different foodstuffs, drugs, beverages, juices and environmental chemical reagents [5]. Many drugs interact with fruit juice such as dihydropyridines, terfenadine, saquinavir, cyclosporine, midazolam, triazolam and verapamil, ergotamine, nimodipine, fluvoxamine, codeine, tramadol, oxycodone, hydrocodone, carbamazepine, imatinib, loperamide, losartan, dextromethorphan, repaglinide, buspirone, amiodarone, dronedarone, quinidine, disopyramide, propafenone, carvedilol, cisapride, felodipine, nicardipine, difedipine, nisoldipine, nitrendipine, sildenafil, tadalafil, vardenafil, dihydrocodeine, omeprazole, zolpidem, methadone, trazodone, praziquantel, albendazole, lovastatin, astemizole and mebendazole etc. [6][7][8][9][10][11][12][13][14][15]. In vitro dissolution acted as a key function in liberating the drug from the tablet matrix and marking for consequent gastrointestinal assimilation. ...
Article
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This study concentrates on dissolution of drug in presence of fruit juice specifically mango juice. This work aspires current research to study the dissolution approach pattern of commercial formulation of metronidazole in Bangladesh commercially available eight brands of metronidazole film coated tablets were studied in gastric medium (pH 1.2). All brands got reasonably higher dissolution release mainly M02 (84.79%), M05 (75.86%), M06 (72.53%) and M07 (86.48%) were released relatively faster than other sample in 15 to 50 minutes. Therefore, Mango juice assists to enhance the therapeutic response of metronidazole on set of quick response.
... Sildenafil is converted into its active metabolite, N-desmethyl sildenafil (UK-103,320) ( Fig. 1), which has a 2.5 fold lower in vitro potency for PDE5. The hepatic metabolism of sildenafil could be stopped by CYP3A4 inhibitors like cimetidine, erythromycin, ritonavir and saquinavir [9], indinavir [10] and grapefruit juice [11]. Moreover, bosentan [12] and other CYP3A4 enhancers induce a faster metabolism of sildenafil reducing its blood concentration. ...
Article
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Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE5) used for the treatment of masculine erectile dysfunction and Pulmonary Arterial Hypertension (PAH). Sildenafil causes vasodilatation; relax of the smooth muscle and reduction of pulmonary arterial pressure. In the liver cytocrome P450 metabolizes sildenafil into its active metabolite, N-desmethyl sildenafil. The determination of plasma levels of sildenafil and N-desmethyl sildenafil could be useful for therapy optimization and pharmacokinetic studies. We have developed and validated a new method for the quantification of sildenafil and its metabolite in human plasma by rapid protein precipitation extraction, using an UPLC system, coupled with a tandem mass spectrometric detector (UPLC-MS/MS). The calibration range was fitted at least square model (r(2)≥0.999), with an accuracy and an intra- and inter-day RSD% (Relative Standard Deviation), both for sildenafil and N-desmethyl sildenafil, lower than 15%, as required by the FDA guidelines; LLOQ, LLOD, ULOQ were 3.9ng/mL, 1.95ng/mL and 1000ng/mL, respectively, for both analytes. Matrix effect, expressed as mean percent deviation of peak areas, was in the range between 2.6% and 5.8%, lower than 15% as required by guidelines. The mean recovery was 83.2 % for sildenafil and 84.5% for N-desmethyl sildenafil. This method has successfully been applied to a clinical pharmacokinetic study of sildenafil and N-desmethyl sildenafil in patients with PAH undergoing cardiac surgery. Copyright © 2015 Elsevier B.V. All rights reserved.
... Grapefruit increased the Cmax of sildenafil by 42% without significant change in the AUC from a single elderly male subject [6]. Jetter et al, [7] reported that the AUC of sildenafil increased 1.23 fold and a trend toward prolongation of tmax after grapefruit juice intake was observed. Cmax did not differ significantly. ...
... 3 SC is cleared predominantly by the hepatic microsomal isoenzymes. 4 The absorption of SC is hindered by fatty meals, 5 with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The main adverse effects of SC are the gastrointestinal effects resulting in dyspepsia, or burning sensation from reflux due to relaxation of the lower esophageal sphincter. ...
Article
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Sildenafil citrate (SC), a drug used to treat erectile dysfunction, is available in tablet form but has three major problems. First, the drug displays inadequate aqueous solubility, which delays the onset of its action. Second, the drug undergoes extensive first-pass metabolism, resulting in a low (40%) bioavailability. Third, the gastrointestinal effects of SC include dyspepsia and a burning sensation. The aim of this research was to prepare SC as a sublingual tablet utilizing soy polysaccharide as novel superdisintegrant to mitigate the abovementioned problems. The solubility of SC in various hydrophilic carrier solutions was estimated in order to prepare the drug as a coprecipitate. Sublingual tablets were prepared and evaluated for hardness, friability, drug content, wetting time, water absorption ratio, in vitro dispersion time, dissolution rate, and stability study. The pharmacokinetic study of the tablets was carried out on healthy volunteers. The results indicated that the co-precipitation of SC with polyvinylpyrollidone K30 enhanced the solubility of SC by more than eight folds. The tablet contained 8% soy polysaccharide as a superdisintegrant and provided a wetting time of 25 seconds, and in vitro dispersion times of 55 seconds. The drug release was found to be 95.6%. The prepared SC sublingual tablet also exhibited a rapid onset of action, and its bioavailability was enhanced 1.68-fold compared with that of the marketed tablets. It can be concluded that SC sublingual tablet is a promising formulation that results in higher solubility, faster dispersion and onset of action, higher release rate, and higher systemic bioavailability.
... etoposide, L-thyroxine). [19][20][21][22] This seeming dichotomy is explained by differential effects on metabolizing enzymes (i.e. CYP3A) and transporters (i.e. ...
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What is known and objective: The management of drug-drug interactions - from recognition of the interaction potential, to addressing the negative consequences - are well-recognized and avoided, or rapidly addressed when identified clinically. Drug-nutrition interactions are no less important than drug-drug interactions in patient care. Unfortunately, beyond those caused by food, these interactions are less commonly recognized or identified and managed. This article will re-introduce the topic of drug-nutrition interactions to clinicians. Comment: Although many clinicians are acutely aware of and vigilant for potential drug-drug interactions, most are less aware of the possibility of drug-nutrition interactions beyond classic food-drug interactions. Interaction can occur between a drug and a nutrient, multiple nutrients, food in general, specific foods or components, or nutrition status. An interaction is considered clinically significant if it alters therapeutic drug response and/or compromises nutrition status. Mechanistically the interactions may be physicochemical reactions, actions at membrane transporters or metabolizing enzymes, or an influence on physiologic function. Appreciating the many types of drug-nutrition interactions will aid the clinician and have the potential to influence patient outcome. What is new and conclusion: Ongoing advances in knowledge about drug and nutrition interactions have potential to improve patient care. Drug-nutrition interactions need to be better recognized, understood on a mechanistic basis, predicted, and managed as necessary.
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Medication and food are frequently consumed together. However, some foods have interactions with medicines by changing key regulators of systemic medication availability. Their consumption is linked to interactions with a wide range of medications. One of the most significant beverages that can be harmful when combined with certain medicines is grapefruit juice. Furanocoumarins' mechanism-based suppression of intestinal cytochrome P450 3A4, which increases the bioavailability of drugs that are substrates, is the main mechanism by which interactions are mediated. There have also been reports of interactions between grapefruit products and uptake transporters such as P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATPs). It has been suggested that polyphenolic substances like flavonoids are what cause the interactions between P-gp and OATP. The amounts of furanocoumarins and flavonoids in the grapefruit product, the amount of juice consumed, the medium PH, and the inherent diversity of enzymes and transporter components in humans can all have an impact on the processes and magnitudes of interactions. In this review, we are going to shed light on clinical trials showing grapefruit juice-drug interactions and what should the health provider do for better clinical care.
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Background: Slamming has been increasing internationally for ten years, mostly among men who have sex with men. Slamming consists of injecting psychostimulants (including new psychoactive substances-NPS) intravenously to increase sexual performance. Objective: The objective of our work was to analyse drug-drug interactions related to slamming. Methods: Drawing upon a reported case of a slam session describing hour by hour the intake of substances, we performed a drug-interaction analysis using international references and a comprehensive literature review. High doses of sildenafil, GBL and 3-MMC were reported during the 40-hour session described. The specific drug-interaction research was performed using 9 references and 65 of the 209 records identified in the literature review. Results: Pharmacological data regarding nonmedicated substances were scarce. Regarding pharmacodynamics, the risk was high at the cardiovascular level and was related to the vasodilatation effect of sildenafil and the adrenergic and serotoninergic properties of stimulants; this risk may increase with usual treatment (involving other vasodilators or central depressants). Regarding pharmacokinetics, the major interactions concerned metabolism by CYP3A4 and CYP2C9, leading to interactions, particularly with HIV medication. Conclusion: This innovative work provides pharmacological information on drugs that are commonly used in slamming, allowing the development of effective medical-management protocols and the provision of risk-reduction counselling.
Article
• The aim of my study was to find the effect of co-administrating orange juice and hesperidin on the bioavailability of metoprolol tartrate in rabbits. • Metoprolol tartrate (10 mg/kg) was given orally to rabbits with hesperidin (10 mg/kg) and with orange juice (6 mL/kg) separately. • The plasma concentrations of metoprolol tartrate were determined using reverse phase-high performance liquid chromatography at 1.5, 1, 2, 4, and 6 h, and the pharmacokinetic parameters were studied. • In comparison to the control group, the AUC of metoprolol tartrate was increased significantly by 68.32% with hesperidin while orange juice substantially reduced the AUC by 37.08%. However, no significant change was observed in Tmax, Kel, and Vd in both groups. The relative bioavailability of metoprolol tartrate with hesperidin was 168.3% as compared to orange juice, that is, 62.9%. • The present study revealed that the concurrent intake of hesperidin with metoprolol tartrate increased its bioavailability while orange juice administration suppressed its bioavailability. The change in bioavailability of metoprolol tartrate might be due to alterations in the activity of cytochrome P450 enzymes involved in the metabolism of metoprolol tartrate. However, the exact mechanism is still not known. These interactions may be of clinical significance.
Article
Nitric oxide (NO), an important endogenous signalling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5'-GMP. Small molecule PDE5 inhibitors (PDE5is) such as sildenafil prolong the availability of cGMP and so enhance NO-mediated signalling. PDE5is are the first line treatment for erectile dysfunction but are also now approved for treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO but this is an expensive option and around 1/3 of newborns are unresponsive resulting in the need for alternative approaches. Here we summarize the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, and then critically review current evidence for the utility of further repurposing of sildenafil as a treatment for PPHN.
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Recent investigations have shown a potential growth in the sales of Grapefruit Juice (GFJ). GFJ contains furanocoumarins, which are potent mechanism-based inhibitors of CYP3A4. Sildenafil, used for erectile dysfunction is metabolized by CYP3A4, so the aim of our review was to understand the interaction between the ingestion of grapefruit juice and the treatment with sildenafil. In August 2018–March 2019 we performed a search in the electronic database PubMed (MEDLINE). The search terms were ‘sildenafil’ AND ‘grapefruit’; ‘sildenafil’ AND ‘naringin’. We searched for studies published without temporal limits, and in English, French, or Spanish. The literature search yielded 12 publications but the review included 2 articles. Studies were published in 2001 and 2002: 1 was settled in Germany, 1 in USA. In both the studies grapefruit led to an increase of peak concentration (Cmax) of sildenafil in plasma. One author showed that grapefruit juice increased the mean oral bioavailability of sildenafil by 23%. Concluding, the important growth in grapefruit juice consumption should be carefully considered by pharmacists and health professionals. Patients undergoing a treatment with sildenafil should be educated about potential adverse reactions.
Chapter
Even after the advent of nerve-sparing procedure a significant percent of patients still develop erectile dysfunction after radical prostatectomy [1]. Modifications in the surgical technique of robotic radical prostatectomy have aimed not only to spare the cavernous nerve but also to minimize any potential harm done from manipulation, traction, or thermal injury of the nerves in addition to sparing the microcirculation surrounding the prostate. The adjunctive measures to optimize early return of erectile function can be subdivided into intraoperative measures designed to optimize nerve preservation and minimize injury to the neurovascular structures surrounding the prostate, and postoperative penile rehabilitation to facilitate early return of erectile function.
Chapter
The treatment of erectile dysfunction (ED) was radically altered following the introduction of oral phosphodiesterase type 5 inhibitors and direct penile injections of vasoactive compounds. However, a large number of men have a poor response to these traditional treatments and require additional management strategies. Currently, novel, minimally invasive strategies are being developed with the hope of delaying placement of an inflatable penile prosthesis, which represents the final phase of ED treatment. This chapter examines the development and role of nanoparticles, the use of stem cells, tissue engineering, and gene therapy for the treatment of ED.
Chapter
For practical purposes, every oral medication must be coconsumed with a beverage. Most physicians and pharmacists admit that, ideally, medications should be taken with a glass of water. However, for many reasons, usually patient preference or convenience, this is often not the case. Occasionally, patients will be instructed by their physicians to take their medication with a certain food or beverage to aid palatability (and hence, compliance), minimize local irritation to the gastrointestinal (GI) tract, or aid in drug absorption.
Chapter
Medication with plants and herbs has been practiced for thousands of years, and a substantial proportion of the world's population is thought to use herbal medicines. Herbal medicines are likely to be taken with prescribed drugs, leading to the risk of herb–drug interactions. Herbal consumption can not only diminish the therapeutic effect of drugs but also give rise to adverse reactions and toxicity. These clinical effects are caused by changes in (i) pharmacokinetics, particularly through inhibition or induction of the cytochrome P450 drug-metabolizing enzymes, and (ii) drug receptor sensitivity. There are many instances where food itself and its constituents have been shown to influence the pharmacokinetics of and response to drugs, sometimes causing substantially diminished therapeutic effects or adverse reactions. Much of the published evidence on herb–drug and food–drug interactions is based on case reports or on pharmacokinetic data alone, and these require substantiation by studies measuring the clinical effects of drugs.
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Sildenafil citrate (Revatio®), an inhibitor of phosphodiesterase type 5 (PDE5), is approved for use in the US, Europe and other countries for the treatment of pulmonary arterial hypertension (PAH). Oral sildenafil 20 mg three times daily added to conventional background therapy was significantly more effective than placebo at increasing exercise capacity in patients with idiopathic PAH or PAH associated with connective tissue diseases or repaired congenital systemic-to-pulmonary shunts. Sildenafil was also associated with improvements in WHO functional class and haemodynamic parameters, and was generally well tolerated. Sildenafil provides benefits in terms of exercise capacity when added to epoprostenol; however, these findings come from a trial that did not use the approved dosage of sildenafil. In conclusion, sildenafil is an effective oral treatment option for patients with PAH. Pharmacological Properties Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate-specific PDE5, and causes relaxation of smooth muscle, in particular, in the pulmonary vasculature and corpus cavernosum. It causes pulmonary vasodilation in patients with pulmonary hypertension and is associated with improvements in mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and, in some studies, cardiac index. At the approved dosage of 20 mg three times daily, sildenafil does not affect systemic blood pressure. Sildenafil potentiates the hypotensive effect of nitrates and these drugs should not be coadministered. Oral sildenafil is absorbed rapidly, reaching peak plasma concentrations after ≈1 hour. It is metabolized principally by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C9, and inducers or inhibitors of these isozymes can affect the clearance of sildenafil. It should not be coadministered with potent CYP3A4 inhibitors. Caution should be exercised when administering sildenafil with bosentan (a CYP3A4 and CYP2C9 inducer), because sildenafil plasma concentrations decrease and bosentan concentrations increase. Sildenafil is predominantly excreted as metabolites in the faeces and has a terminal elimination half-life of 3—5 hours. The major (N-desmethyl) metabolite of sildenafil has an in vitro potency approximately half that of the parent compound. Therapeutic Efficacy The Efficacy of sildenafil in adults with idiopathic PAH was demonstrated in a large, well designed, 12-week trial (SUPER-1). Dosages included 20 (the approved dosage), 40 and 80 mg three times daily. At baseline, most patients were in WHO functional class II or III and had a mean 6-minute walking distance of 344 m. All dosages of sildenafil significantly increased the placebo-corrected 6-minute walking distance (the primary endpoint) by 45—50 m after 12 weeks, but there was no significant difference in efficacy between the three dosages. At the approved dosage, sildenafil also led to significant increases in the proportion of patients improving by at least one functional class and exhibiting significant improvements in haemodynamic parameters, including mean PAP and PVR. Health-related quality of life (all dosages combined) significantly improved with sildenafil compared with placebo for domains addressing the physical impact of PAH and general health. In an open-label extension study of SUPER-1 (SUPER-2) in which all patients received sildenafil 80 mg three times daily (higher than the approved dosage), efficacy was maintained to 1 year and, among 141 patients with idiopathic PAH, 1-year survival was 96% compared with a predicted survival of 71%. Studies comparing sildenafil with other specific PAH therapies, or evaluating combination therapy, all used dosages higher than the approved dosage. In a small, 16-week study in patients with PAH (functional class III), there was no significant difference between sildenafil and bosentan for change in right ventricular mass (primary endpoint) or 6-minute walking distance. The combination of sildenafil with intravenous epoprostenol was evaluated in a large, well designed, 16-week trial in patients with PAH. The addition of sildenafil to epoprostenol significantly increased 6-minute walking distance (placebo-corrected increase of 26 m; p = 0.0009) and improved most haemodynamic parameters compared with placebo. Tolerability Sildenafil was generally well tolerated by patients with PAH. Based on placebo-subtracted incidences, the most common adverse events with sildenafil 20 mg three times daily in SUPER-1 were epistaxis, headache, dyspepsia, flushing, insomnia and erythema. Retinal haemorrhage occurred in 1.4% of the sildenafil 20 mg three times daily group (vs 0% for placebo); most patients had risk factors for bleeding. Epistaxis was more common among patients with connective tissue disorders than in those with idiopathic PAH, and concomitant use of vitamin K antagonists also increased the risk of epistaxis. Adverse events reported during combination therapy with sildenafil and epoprostenol were consistent with events reported during SUPER-1.
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After the advent of four type 5 phosphodiesterase inhibitors (PDEI 5), viz. sildenafil, tadalafil, vardenafil, and udenafil, designed for the treatment of erectile dysfunction both physicians and patients found themselves faced with the problem of choosing an optimal therapeutic option. This paper contains comparative data on the efficacy and safety of different PDEI 5. The approaches to the rational choice of these preparations for the treatment of patients presenting with cardiovascular and endocrine diseases are discussed. Comparative controlled clinical studies failed to yield definitive information about advantages of one or another agent representing this group of pharmaceutical products. Nevertheless, the currently available data permit to draw the conclusion that the use of vardenafil and tadalafil ensures better compliance of patients with the prescribed therapy. Certain authors advocate the desirability of vardenafil application to the treatment of patients presenting with a background pathology. It is emphasized that all available PDEI 5 have a beneficial safety profile, with wardenafil being virtually free from adverse side effects.
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Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro to in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0-72 h. Relative to water, GFJ increased the geometric mean loperamide AUC significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (K I, 5.0 ± 0.9 μM; kinact, 0.38 ± 0.02 min(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.
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In vitro dissolution of ten brands of diclofenac sodium sustained release matrix tablets were studied to determine the effect of fruit juice in the bioavailability of diclofenac. Significant reduction was observed in the release rate at all collected brands, where except sample D7 and D8 others were not fulfill the USP in vitro dissolution specification when administered with fruit juice. Therefore to avoid drug therapeutic failures and of the drug in the systemic circulation, ingestion of the juice with diclofenac sodium should be discouraged. INTRODUCTION: Diclofenac is commonly prescribed as non-steroidal anti-inflammatory agent (NSAIA) that is taken to reduce inflammation, reducing pain in conditions such as acute injury, musculoskeletal, especially to treat rheumatoid arthritis, osteoarthritis, syondyarthritis, gout attacks, pain management in case of kidney stone. It is very effective in the management of menstrual pain, ovulatory pain, acute migraines, post-operative and post-traumatic pain, female breast cancer and pain associated with bony metastases 1 .
Article
For some years drugs of several different classes have been available in Germany for the treatment of pulmonary arterial hypertension (PHT): prostanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors. To-date all relevant studies have consistently shown improvement in the 6-minute walking test (Iloprost, Treprostinil, Bosentan, Sitaxentan, Ambrisentan, Sildenafil). Results have not been consistent when the end-point has been an improvement in New York Heart Association (NYHA) class III or in the time to clinical worsening. Despite the good safety data for all drugs approved in Germany in the treatment of PHT, there are some clinically relevant interactions and significant contraindications. The availability of several options demands a detailed knowledge of studies to optimize safety and success in the treatment of PHT. Placebo-control mortality studies are not available for ethical reasons for those drugs that have been approved in Germany. But cohort analyses using historical survival rates have demonstrated a impressive improvement in survival of patients with PHT. Although there has been great progress in the treatment of PHT, a cure of this grave disease is not yet possible.
Chapter
Objectives • Provide a comprehensive overview of the clinical interactions of grapefruit or other fruit juices with medications to cause altered pharmacokinetics and potential clinical drug response. • Focus primarily on the extensive literature of interactions determined by modulation of drug metabolism mediated by intestinal CYP3A4. Established/predicted and interacting/non-interacting medications, important adverse events and possible beneficial effects and clinical recommendations are discussed. • Address more recent research on interactions determined most likely by changed presystemic efflux/uptake drug transport.
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Aims To investigate the effect of the antiretroviral protease inhibitors saquinavir (soft gelatin capsule) and ritonavir on the pharmacokinetic properties and tolerability of sildenafil and to investigate the effect of sildenafil on the steady-state pharmacokinetics of saquinavir and ritonavir. Methods Two independent, 8 day, open, randomized, placebo-controlled, parallel-group studies (containing a double-blind crossover phase) were conducted at Pfizer Clinical research units (Canterbury, UK. and Brussels, Belgium). Twenty-eight healthy male volunteers entered each study. In each study, volunteers were randomized (n = 14 per group) to receive sildenafil on day 1 followed by a 7-day treatment period (days 2–8) with saquinavir or placebo (Study I) or ritonavir or placebo (Study II). Sildenafil or placebo (Study I and Study II) was administered alternately on day 7 or day 8, depending on initial randomization. The effect of saquinavir and ritonavir on the pharmacokinetics of sildenafil and its primary circulating metabolite (UK-103, 320) and the effect of single-dose sildenafil on the steady-state pharmacokinetics of saquinavir (1200 mg three times daily) and ritonavir (500 mg twice daily) were determined. The safety and tolerability of sildenafil coadministered with saquinavir or ritonavir were also assessed. Results Both protease inhibitors significantly increased Cmax, AUC, tmax and t½ values for both sildenafil and UK-103, 320. Ritonavir showed a significantly greater effect than saquinavir with increases in sildenafil AUC and Cmax of 11-fold (95% CI: 9.0, 12.0) and 3.9-fold (95% CI: 3.2, 4.9), respectively. This compared with increases of 3.1-fold (95% CI: 2.5, 4.0) and 2.4-fold (95% CI: 1.8, 3.3) for coadministration with saquinavir. In contrast, the steady-state pharmacokinetics of saquinavir and ritonavir were unaffected by sildenafil. The increases in systemic exposure to sildenafil and UK-103, 320 were not associated with an increased incidence of adverse events or clinically significant changes in blood pressure, heart rate or ECG parameters. Conclusions These results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildenafil presumably through inhibition of CYP3A4. The more pronounced effect of ritonavir may be attributed to its additional potent inhibition of CYP2C9. No change in safety or tolerability was observed when sildenafil was coadministered with either protease inhibitor. However, given the extent of the interactions, a lower sildenafil starting dose (25 mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25 mg in a 48 h period for patients receiving ritonavir.
Article
Objective To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam.Methods Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of α-hydroxymidazolam.ResultsIn comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% ± 3% (water) to 35% ± 3% (Grapefruit juice; mean ± SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of α-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged.Conclusions Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.Clinical Pharmacology & Therapeutics (1995) 58, 20-28; doi: 10.1016/0009-9236(95)90068-3
Article
Objective: To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine.Methods: Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied.Results: Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentrations (Cmax), and apparent elimination half-life (t1 2); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t1 2 but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t1 2. Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmax but not with relative felodipine t1 2, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination.Conclusions: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall.
Article
Objectives: The prevalence of erectile dysfunction in HIV-infected men is estimated to be 33%. Sildenafil citrate (Viagra; Pfizer Ltd, Sandwich, Kent, UK) is the first oral drug for this condition. Since sildenafil and the protease inhibitors are both metabolized by, and act as inhibitors of cytochrome P450 3A4, we evaluated the pharmacokinetics of the combination sildenafil plus indinavir in HIV-infected patients. Design and methods: Six patients at steady state in treatment with indinavir participated in the study. On the first day blood samples for indinavir assay were drawn at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. On the second study day patients received a single dose of 25 mg of sildenafil in addition to their routine morning medication. Blood samples were taken as described. Separated plasma was stored at -80°C until analysis by high performance liquid chromatography. In a parallel study, the effect of indinavir, ritonavir, saquinavir and nelfinavir on the in vitro hepatic metabolism of sildenafil was assessed. Results: The geometric mean area under the concentration curve for 0-8h (AUC0-8h) and maximum plasma concentration (Cmax) for indinavir were 19.69μg/mlh (range, 9.19-31.99μg/mlh) and 7.02μg/ml (range, 2.33-16.17μg/ml), respectively, on the first study day. In the presence of sildenafil, the mean AUC0-8h and Cmax of indinavir were 22.37μg/mlh [range, 10.08-37.25μg/mlh; 95% confidence interval (CI) for difference between means, -15 to 13.25) and 9.11μg/ml (range, 3.41-22.78μg/ml; 95% CI, -13 to 6.37), respectively. The geometric mean AUC0-8h and Cmax for sildenafil were 1631 ng/mlh (range, 643-2970 ng/mlh) and 384 ng/ml (range, 209-766 ng/ml) respectively. The AUC for sildenafil was 4.4 times higher than data from historical controls given either 50mg or 100 mg of sildenafil and dose normalized to 25 mg. Indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro [concentration producing 50% inhibition of control enzyme activity (IC50) = 0.39 ± 0.17 μM, mean ± SD]. Conclusions: Co-administration of sildenafil 25 mg did not significantly alter the plasma indinavir levels. However, plasma sildenafil AUC was markedly increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in this clinical setting.
Article
Four coumarins, four psoralens and two methoxyflavones were isolated and identified from the peel oil of grapefruit. Five of these compounds are reported as constituents of grapefruit oil for the first time, one of which, 5[(3,7-dimethyl-6-epoxy-2-octenyl) oxy]psoralen is a new natural product.
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The statistical analysis of bioequivalence assessment has been consolidated in recent years through the work of Schuirmann [1987], Westlake [1988] and Hauschke et al. [1990], and this has been reflected in the CPMP Note for Guidance on Bioavailability and Bioequivalence and in the joint recommendations of the APV (International Association for Pharmaceutical Technology) and ZL (Central Laboratories of German Pharmacists) during a recent workshop in support of EC-Guidelines [Blume et al. 1990]. Since the decision procedure based on the inclusion of the shortest 90%-confidence interval in the bioequivalence range is the procedure of choice, and as this is equivalent to the two one-sided tests procedure, the sample size determination is based on the power of the latter. Following the approach of Phillips [1990] for the additive model, corresponding nomograms for the more relevant multiplicative model are given in this paper for various ratios of the expected means for test and reference and various coefficients of variation.
Article
Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A enzymes. Ketoconazole and itraconazole can increase the area under the concentration-time curve [AUC(0-infinity)] of triazolam, a substrate of CYP3A, by more than twenty times. In this randomized crossover study the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of triazolam was investigated. Ten healthy young subjects received a single 0.25 mg dose of triazolam with either 250 ml grapefruit juice or water. Plasma concentrations and effects of triazolam were measured up to 17 hours. Grapefruit juice increased the AUC(0-infinity) of triazolam in each subject and the peak concentration in nine of the 10 subjects. The mean AUC(0-infinity) of triazolam was increased 1.5-fold (p < 0.001) and the peak concentration was increased 1.3-fold (p < 0.05) by grapefruit juice. Grapefruit juice postponed the peak time of triazolam from 1.6 hours to 2.5 hours (p < 0.05). Grapefruit juice increased the effects of triazolam slightly; drowsiness was significantly (p < 0.05) enhanced. Grapefruit juice can increase the plasma concentrations and effects of oral triazolam.
Article
The objective of the presented two-way randomized crossover study was to investigate whether repeated doses of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h) enhanced bioavailability of diltiazem (120 mg, orally) in nine healthy male subjects. Grapefruit juice did not alter AUC or cmax of diltiazem, whereas the half life experienced a slight, but statistically significant, increase (4.1 +/- = 1.2 vs 5.1 +/- 0.7 h). The N-demethyldiltiazem/diltiazem and deacetyldiltiazem/diltiazem ratios were not affected by grapefruit juice intake, which indicates that these metabolic pathways are not inhibited. Whereas bioavailability of some calcium channel antagonists of the dihydropyridine type metabolized via the same cytochrome P450 has been shown to be dramatically increased by grapefruit juice intake, the bioavailability of the benzothiazepine calcium channel antagonist diltiazem remained unchanged. This suggests that factors other than biotransformation may contribute to the clear effect of grapefruit juice on the bioavailability of those substances.
Article
The demonstration that concomitant administration of drug B does not affect the pharmacokinetics of drug A can be adequately handled as an equivalence problem. Administration of drug A alone serves as reference and simultaneous administration of drugs A and B as test situation. The range of clinically acceptable variation in the pharmacokinetic characteristics of drug A defines the equivalence range. This will usually correspond to the bioequivalence range accepted for the comparison of different formulations of drug A. Equivalence, i.e. lack of pharmacokinetic interaction, is concluded if the 90%-confidence interval for the ratio (difference) of the expected medians for test and reference is entirely within the equivalence range. This decision procedure ensures that the consumer risk of incorrectly concluding "lack of interaction" is limited to 5%. Moreover, the producer risk of incorrectly concluding "interaction" can be controlled by appropriate sample sizes.
Article
The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.
Article
Grapefruit juice increases the oral availability of a variety of CYP3A4 substrates. It has been shown that recurrent grapefruit juice ingestion results in a loss of CYP3A4 from the small bowel epithelium. We now show that the reduction in intestinal CYP3A4 concentration is rapid; a 47% decrease occurred in a healthy volunteer within 4 hr after consuming grapefruit juice. To identify the specific components of the juice responsible for this effect, we used a recently developed Caco-2 cell culture model of human intestinal epithelium that expresses catalytically active CYP3A4. We found that grapefruit oil and two furanocoumarin constituents (6', 7'-dihydroxybergamottin and a closely related dimer) caused a dose-dependent fall in CYP3A4 catalytic activity and immunoreactive CYP3A4 concentration. The effect was selective in that concentrations of CYP1A1 and CYP2D6 did not fall, consistent with previous results obtained in vivo. Assays of various juices confirmed that 6',7'-dihydroxybergamottin is the major furanocoumarin present and, although its concentration varies significantly among types and brands of grapefruit juice, it is consistently present in concentrations exceeding the IC50 (1 microM) for loss of midazolam 1'-hydroxylase activity determined in the Caco-2 cells. Studies with recombinant CYP3A4 revealed that 6', 7'-dihydroxybergamottin is a mechanism-based inactivator, which supports the idea that loss of CYP3A4 results from accelerated degradation of the enzyme. We conclude that the effect of grapefruit juice on oral availability of CYP3A4 substrates can be largely accounted for by the presence of 6',7'-dihydroxybergamottin although other furanocoumarins probably also contribute.
Article
Four components were isolated from grapefruit juice that inhibit human CYP3A-mediated drug oxidation. The structures of these compounds were identified as furocoumarin derivatives by absorption spectra, APCI-liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance after their purification by reversed-phase high performance liquid chromatography. They include two new furocoumarins, 4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl)ethyl]-4-methyl-6- (7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimeth yl- 2-octenyl] oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyl-I- (1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4- hexenyl] oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-4). These furocoumarins are strong candidates for causative agents of grapefruit juice-mediated drug interaction, because of an inhibition potential that is equal to or stronger than the prototypical CYP3A4 inhibitor, ketoconazole, on liver microsomal testosterone 6 beta-hydroxylation.
Article
Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.
Article
1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or [14C]-sildenafil (Viagra). 2. In man, absorption from the gastrointestinal tract was essentially complete. With the exception of male rat, Tmax occurred at approximately 1 h or less. Bioavailability was attenuated by pre-systemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-2 l/kg) but was greater in dog (5.2 l/kg), due to lower plasma protein binding (84 versus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the various species. 5. After single oral or intravenous doses of [14C]-sildenafil, the majority of radioactivity was excreted in the faeces of all species. No unchanged drug was detected in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. 7. Sildenafil was the major component detected in human plasma. Following oral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.
Article
Grapefruit juice increases the oral bioavailability of several drugs metabolized by cytochrome P450 3A4. This study investigated the influence of grapefruit juice on the pharmacokinetics of oral cisapride, a substrate of CYP3A4. Fourteen healthy volunteers received in random order 10 mg cisapride (Prepulsid) with 250 mL water or grapefruit juice after an overnight fast. Blood samples were taken for 25 hours and urine was collected for 36 hours after dosing. Plasma concentrations of cisapride and urinary norcisapride were measured by HPLC. The influence of grapefruit juice on pharmacokinetic parameters (mean +/- SD) was assessed with the Wilcoxon matched pairs test for 13 subjects (1 subject did not fast as instructed). Grapefruit juice increased cisapride maximum measured plasma concentration (Cmax; water, 65+/-398 ng/mL; grapefruit juice, 87+/-40 ng/mL; P = .009) and area under the plasma concentration-time curve from 0 to 25 hours [AUC(0-25); water, 418+/-280 h x ng/mL; grapefruit juice, 580+/-289 h x ng/mL; P = .005] and prolonged the time to reach Cmax (water, 1.26+/-0.36 hours; grapefruit juice, 1.72+/-0.55 hours; P = .02). Half-life was not affected. Urinary norcisapride recovery was similar and thus the partial apparent metabolic clearance to norcisapride was lower (P = .046) after grapefruit juice (89.5+/-41.2 mL/min) than after water (121.5+/-54.7 mL/min). There was considerable interindividual variation in the grapefruit juice effect [range of AUC(0-25) grapefruit juice/water ratio, 0.90 to 2.65). Grapefruit juice increases the oral bioavailability of cisapride, with large interindividual variation in the change in Cmax and AUC. Because cisapride has a wide therapeutic index, the interaction may not be of major clinical significance for efficacy, but further studies are necessary at steady state to rule out the possibility of side effects in susceptible individuals.
Article
Sildenafil is an oral therapy for erectile dysfunction of a broad range of causes. By selectively inhibiting phosphodiesterase type 5, it allows corpus cavernosum smooth muscle to relax, potentiating erections during sexual stimulation. Blood pressure is reduced transiently by sildenafil, but more marked hypotension may occur during concurrent administration of sildenafil and organic nitrates; this combination is contraindicated. Sildenafil is rapidly absorbed, with dose-proportional peak plasma concentrations within 1 hour of administration. The elimination half-life is 3 to 5 hours. Dosages usually begin at 50mg taken when needed =1 hour before sexual activity no more than once daily. The maximum dose is 100mg when needed once daily and lower doses (e.g. 25mg) may be used in elderly patients and those with hepatic or renal impairment or receiving cytochrome P450 enzyme CYP3A4 inhibitors, such as ritonavir, saquinavir, ketoconazole, erythromycin or cimetidine. More than 3000 patients with erectile dysfunction of organic (e.g. diabetes or spinal cord injury), psychogenic or mixed origin received sildenafil 5 to 100mg or placebo in fixed- or titrated-dose trials. Sildenafil was associated with dose-related improvements in the frequency, hardness and duration of erections and in patients' abilities to achieve and maintain erections adequate for successful sexual intercourse. In titrated-dose trials, the most commonly effective doses were 50 or 100mg, although lower doses were effective in some patients. Sildenafil was significantly more effective than placebo in erectile dysfunction of all tested causes. The efficacy of sildenafil was not affected by patient age (> or < or =65 years) or by antihypertensive or antidepressant medications. The drug was effective in patients with severe erectile dysfunction. Efficacy was maintained in long term (1-year) studies. Sildenafil also appears to improve the quality of life of both patients and their sexual partners. Common adverse events associated with sildenafil were transient and mild or moderate and included headache, flushing, dyspepsia, nasal congestion and abnormal vision. Tolerability was maintained in long term (< or =1 year) studies. No serious sildenafil-related adverse events occurred in clinical trials; cardiovascular events seen in postmarketing surveillance generally occurred in patients with other known risk factors. CONCLUSIONS: Sildenafil is an effective oral treatment in men with erectile dysfunction. It was significantly superior to placebo in improving erections and allowing successful penetrative sexual intercourse. Although its place in disease management is still emerging and there are contraindications to its use, if preliminary positive reports are confirmed, sildenafil will be the pre-eminent first-line therapy for erectile dysfunction.
Article
The in vitro biotransformation of sildenafil to its major circulating metabolite, UK-103,320, was studied in human liver microsomes and in microsomes containing heterologously expressed human cytochromes. In human liver microsomes, the mean K(m) (+/-S.E. ) was 14.4 +/- 2.0 microM. A screen of the chemical inhibitors omeprazole (10 microM), quinidine (10 microM), sulfaphenazole (10 microM), and ketoconazole (2.5 microM) only revealed detectable inhibition with ketoconazole. Sildenafil biotransformation (36 microM) was inhibited by increasing concentrations of ketoconazole and ritonavir (IC(50) values less than 0.02 microM), which are established cytochrome P450 (CYP) 3A4 inhibitors. Using microsomes containing cDNA-expressed cytochromes, UK-103,320 formation was found to be mediated by four cytochromes: CYP3A4, -2C9, -2C19, and -2D6. Estimated relative contributions to net intrinsic clearance were 79% for CYP3A4 and 20% for CYP2C9; for CYP2C19 and -2D6, estimated contributions were less than 2%. These results demonstrate that CYP3A4 is the primary cytochrome mediating UK-103,320 formation and that drugs that inhibit CYP3A4 are likely to impair sildenafil biotransformation.
Article
With juices of grapefruit and related fruits, possible relationships between contents of six different furanocoumarins and extents of inhibition of microsomal CYP3A activity have been studied in vitro. Microsomal CYP3A-mediated testosterone 6beta-hydroxylation was inhibited by the addition of a fruit juice (2.5%, v/v) from eight different grapefruit sources, two sweeties, three pomelos, and one sour orange, whereas no clear inhibition was observed with two sweet orange juices. The inhibitory component in grapefruit juice resides mainly in the precipitate rather than in the supernatant after centrifugation. Higher amounts of (R)-6',7'-dihydroxybergamottin (DHB) were distributed in the supernatant, whereas GF-I-1, GF-I-2, GF-I-4, and the newly isolated GF-I-5 and GF-I-6 were detected predominantly in the precipitate. Mixing of five representative furanocoumarins at their detectable levels in grapefruit juice reproduced roughly the inhibitory potencies of grapefruit juice, but omission of any of the components resulted in decreased potencies. These results suggested that all the major furanocoumarins contributed to the CYP3A inhibitory properties of grapefruit juice. Furthermore, all six furanocoumarins showed stronger CYP3A inhibitory potencies after preincubation in the presence of NADPH, suggesting that both competitive and mechanism-based inhibition occur in a grapefruit juices-drug interaction.
Article
Five compounds including furanocoumarin monomers (bergamottin, 6', 7'-dihydroxybergamottin (DHB)), furanocoumarin dimers (4-¿¿6-hydroxy-71-¿(1-hydroxy-1-methyl)ethyl-4-methyl-6-(7-oxo-7H- furo¿3,2-g1benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl- 2-octenyl]oxy]-7H-furo[3,2-g]¿1benzopyran-7-one (GF-I-1) and 4-¿¿6-hydroxy-7¿¿4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo¿3, 2-g1benzopyran-4-yl)-4-hexenylŏxy-3, 7-dimethyl-2-octenylŏxy-7H-furo¿3,2-g1benzopyran-7-one (GF-I-4)), and a sesquiterpene nootkatone have been isolated from grapefruit juice and screened for their inhibitory effects toward human cytochrome P450 (P450) forms using selective substrate probes. Addition of ethyl acetate extract of grapefruit juice into an incubation mixture resulted in decreased activities of CYP3A4, CYP1A2, CYP2C9, and CYP2D6. All four furanocoumarins clearly inhibited CYP3A4-catalyzed nifedipine oxidation in concentration- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4. Of the furanocoumarins investigated, furanocoumarin dimers, GF-I-1 and GF-I-4, were the most potent inhibitors of CYP3A4. Inhibitor concentration required for half-maximal rate of inactivation (K(I)) values for bergamottin, DHB, GF-I-1, and GF-I-4 were calculated, respectively, as 40.00, 5. 56, 0.31, and 0.13 microM, whereas similar values were observed on their inactivation rate constant at infinite concentration of inhibitor (k(inact), 0.05-0.08 min(-1)). Apparent selectivity toward CYP3A4 does occur with the furanocoumarin dimers. In contrast, bergamottin showed rather stronger inhibitory effect on CYP1A2, CYP2C9, CYP2C19, and CYP2D6 than on CYP3A4. DHB inhibited CYP3A4 and CYP1A2 activities at nearly equivalent potencies. Among P450 forms investigated, CYP2E1 was the least sensitive to the inhibitory effect of furanocoumarin components. A sesquiterpene nootkatone has no significant effect on P450 activities investigated except for CYP2A6 and CYP2C19 (K(i) = 0.8 and 0.5 microM, respectively).
Article
A method for the determination of three furocoumarins containing two new chemicals (GF-I-1 and GF-I-4) in commercially available grapefruit juice and grapefruit itself was developed using high-performance liquid chromatography (HPLC). These components isolated from grapefruit juice have 5-geranyloxyfurocoumarin dimer structures showing extremely high affinities for a form of cytochrome P450 (CYP3A4). Considerable differences were observed on the contents among commercial brands and also batches. The contents were determined to be 321.4+/-95.2 ng/ml GF-I-1, 5641.2+/-1538.1 ng/ml GF-I-2 and 296.3+/-84.9 ng/ml GF-I-4 in twenty-eight white grapefruit juices. These chemicals were not detected in beverages from orange, apple, grape and tangerine, except that trace amount of GF-I-2 and GF-I-4 were found in lemon juice. The average levels of these furocoumarins were lower in the juice from red grapefruit than a white one. The highest level of these components were found in the fruit meat.
Article
Grapefruit juice is a potent inhibitor of CYP3A4-mediated drug metabolism. We wanted to investigate how long the inhibitory effect of grapefruit juice lasts, with the CYP3A4 substrate simvastatin used as a model drug. This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40 mg simvastatin with water (control), with "high-dose" grapefruit juice (200 mL double-strength grapefruit juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of "high-dose" grapefruit juice. For safety reasons, the study was performed in three parts to allow simvastatin-free days between the study days. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography-tandem mass spectrometry up to 12 hours. When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-infinity)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When simvastatin was administered 24 hours after ingestion of the last dose of grapefruit juice, the Cmax and AUC(0-infinity) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of grapefruit juice, the Cmax and AUC(0-infinity) were increased 1.5-fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control. Seven days after ingestion of grapefruit juice, no differences in the Cmax or AUC(0-infinity) of simvastatin were seen. The mean Cmax and AUC(0-infinity) of simvastatin acid were increased 5.0-fold and 4.5-fold, respectively (P < .001), compared with control when simvastatin was taken with grapefruit juice and 1.7-fold (P < .01) when it was taken 24 hours after ingestion of grapefruit juice. After an interval of 3 or 7 days between ingestion of grapefruit juice and simvastatin, the pharmacokinetic variables of simvastatin acid did not differ significantly from those in the control phase. When simvastatin is taken 24 hours after ingestion of "high-dose" grapefruit juice, the effect of grapefruit juice on the AUC of simvastatin is only about 10% of the effect observed during concomitant intake of grapefruit juice and simvastatin. The interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice.
Article
Our objective was to determine whether Seville orange juice produces a grapefruit juice-like interaction with felodipine and whether bergamottin, 6',7'-dihydroxybergamottin, or other furocoumarins are involved. In a randomized three-way crossover design, 10 volunteers received a felodipine 10-mg extended-release tablet with 240 mL of Seville orange juice, dilute grapefruit juice (that contained equivalent total molar concentrations of bergamottin plus 6',7'-dihydroxybergamottin), or common orange juice (negative control). The pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined. Juice concentrations of furocoumarins were measured. CYP3A4 inhibitory activity of newly identified furocoumarins was assessed. The felodipine area under the plasma concentration-time curve was increased by 76% and 93% after Seville orange juice and grapefruit juice ingestion, respectively, compared with common orange juice. The effects of Seville orange juice and grapefruit juice were similar in that the felodipine maximum concentration was augmented while the terminal elimination half-life was unchanged and the dehydrofelodipine area under the plasma concentration time-curve was increased, but the dehydrofelodipine-felodipine area under the plasma concentration-time curve ratio was reduced. Bergamottin and 6',7'-dihydroxybergamottin concentrations were 5 and 36 micromol/L, respectively, in Seville orange juice and were 16 and 23 micromol/L, respectively, in dilute grapefruit juice. A newly identified furocoumarin, bergapten, was detected only in Seville orange juice (31 micromol/L), and it was found to be a mechanism-based inhibitor of recombinant CYP3A4. Relative to the control, 6',7'-dihydroxybergamottin (10 micromol/L) inhibited CYP3A4 activity in cultured intestinal epithelial cells by 93%, whereas bergapten (10 micromol/L) inhibited the activity by only 34%. Seville orange juice and grapefruit juice interact with felodipine by a common mechanism, which is probably inactivation of intestinal CYP3A4. Bergamottin and 6',7'-dihydroxybergamottin may be "marker substances" in foods for this interaction. The lack of interaction between Seville orange juice and cyclosporine (INN, ciclosporin) suggests that grapefruit juice may also inhibit intestinal P-glycoprotein, whereas Seville orange juice may selectively "knock out" intestinal CYP3A4.
Article
This study was designed to establish a simple and reliable assay method that could be routinely used in the clinical laboratory setting using liquid extraction and high-performance liquid chromatography (HPLC). In addition, a case of potential interaction of grapefruit juice with sildenafil citrate is presented. The peaks of sildenafil (measured as sildenafil salt) and internal standard were identified with an ultraviolet detector at 230 nm and detection limit at 10 ng/mL. In a single elderly male patient, grapefruit juice increased the Cmax of sildenafil by 42% (1067.7 ng/mL to 1517.0 ng/mL) although AUC was not significantly altered (4082.9 ng x h/mL to 4171.9 ng x h/mL) by grapefruit juice. Sildenafil could be determined in a simple and reliable method using HPLC with liquid extraction. This case indicated that grapefruit juice might increase the Cmax of sildenafil without significant change in AUC. A further study with an appropriate number of subjects is needed before determining the degree of interaction between grapefruit juice and sildenafil.
Article
Since its approval by the US Food and Drug Administration in March 1998, sildenafil citrate has been used by millions of men for the treatment of erectile dysfunction. Recent studies and consensus reports have expanded our understanding of its efficacy, safety, contraindications, and drug interactions. This paper reviews recent studies of the efficacy of sildenafil, its adverse effects and drug interactions, and socioeconomic factors involved in its use, with a focus on specific patient populations (prostate cancer, diabetes mellitus, ischemic heart disease, spinal cord injuries, neurologic disorders). Clinical studies, case reports, and commentaries and editorials concerning sildenafil published in the international literature between January 1999 and August 2000 were identified through searches of MEDLINE, PREMEDLINE, and International Pharmaceutical Abstracts, using the terms sildenafil, Viagra, and erectile dysfunction. Sildenafil has demonstrated effectiveness in men with erectile dysfunction associated with prostatectomy, radiation therapy, diabetes mellitus, certain neurologic disorders, and drug therapy (eg, selective serotonin reuptake inhibitors [SSRIs]). It has not been as effective in women with sexual dysfunction, with the exception of SSRI-associated sexual dysfunction. Some disorders unrelated to sexual dysfunction (eg, esophageal motility dysfunction) may also respond to sildenafil. In the general population, sildenafil is considered to have an acceptable tolerability profile; however, patients with moderate to severe cardiovascular disease or those taking nitrate therapy are at increased risk for potentially serious cardiovascular adverse effects with sildenafil therapy. In addition, patients taking drugs that inhibit the cytochrome P450 3A4 isozyme, which metabolizes sildenafil, may experience increased drug concentrations and possible toxicity from normal doses of sildenafil. Sildenafil is an effective first-line therapy for erectile dysfunction in men. The decision to prescribe this agent should include such considerations as the cost-risk-benefit balance, patient access, drug distribution pathways, and prescription drug coverage.
Article
To characterize the cytochrome P450 (CYP) enzymes responsible for the N-demethylation of sildenafil to its main metabolite, UK-103 320, to investigate the potential inhibitory effects of sildenafil on CYP enzymes and to evaluate the potential of selected drugs to affect sildenafil metabolism. The metabolic pathways of sildenafil N-demethylation were studied using human liver microsomes, as well as microsomes expressing individual human CYP enzymes. Further studies to identify the individual enzymes were performed at 2.5 and 250 microM sildenafil, and employed a combination of chemical inhibition, correlation analysis, and metabolism by expressed recombinant CYP enzymes. In addition, the effect of sildenafil on the activity of the six major drug metabolizing enzymes was investigated. Sildenafil conversion was found to be mediated by at least two CYP enzymes, for which the mean kinetic parameters were Km1 = 6(+/-3 microM), Km2 = 81(+/-45 microM), Vmax1 = 22(+/-9 pmol) and Vmax2 = 138(+/-77 pmol) UK-103 320 formed min(-1) mg(-1). At 250 microM sildenafil, N-demethylation was primarily mediated through the low-affinity, high-Km enzyme (approximately 83%), whilst at 2.5 microM there was a greater role for the high-affinity, low-Km enzyme (approximately 61%). Ketoconazole strongly inhibited metabolism at both sildenafil concentrations and was the only significant inhibitor at 250 microM sildenafil. At the lower sildenafil concentration, sulphaphenazole and quinidine also inhibited formation of UK-103 320. Overall, 75% or more of the N-demethylation of sildenafil at any concentration is probably attributable to CYP3A4. These results were supported by experiments using expressed human CYP enzymes, in which only CYP3A4 and CYP2C9 exhibited substantial sildenafil N-demethylase activity (respective Km values of 221 microM and 27 microM). Sildenafil metabolism was inhibited by potent CYP3A4 inhibitors which are used clinically, but was found to be only a weak inhibitor of drug metabolizing enzymes itself, the strongest inhibition occurring against CYP2C9 (Ki = 80 microM). Evidence is provided for CYP3A4 and to a lesser extent CYP2C9-mediated metabolism of sildenafil. There is the possibility that elevated plasma concentrations of sildenafil could occur with coadministration of known inhibitors of CYP2C9 or CYP3A4. Since peak plasma concentrations of clinical doses of sildenafil are only 200 ng ml(-1) ( approximately 0.4 microM) it is very unlikely that sildenafil will significantly alter the plasma concentration of other compounds metabolized by cytochrome P450 enzymes.
Klinisch-pharmakologisches Profil: Silde-nafilzitrat (Viagra)
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de Mey C. Klinisch-pharmakologisches Profil: Silde-nafilzitrat (Viagra). Klin Pharmakol Akt 1998;9:87-90.
Determination of sildenafil citrate in
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Lee M, Min DI. Determination of sildenafil citrate in
Grapefruit juice (GFJ) inhibits hepatic and intestinal CYP3A4 dose-dependently
  • Burke M J Veronese
  • E Dorval
  • E Pequignot
  • S Waldman
  • Greenberg
Veronese M, Burke J, Dorval E, Pequignot E, Waldman S, Greenberg H. Grapefruit juice (GFJ) inhibits hepatic and intestinal CYP3A4 dose-dependently. Clin Pharma-col Ther 2000;67:151.
E-mail: alexander.jetter@medizin.uni-koeln.de Copyright © 2002 by the American Society for Clinical Pharmacol-ogy and Therapeutics. 0009-9236
  • Köln
  • Germany
Köln, Germany. E-mail: alexander.jetter@medizin.uni-koeln.de Copyright © 2002 by the American Society for Clinical Pharmacol-ogy and Therapeutics. 0009-9236/2002/$35.00 + 0 13/1/121236 doi:10.1067/mcp.2002.121236 References