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The effects of grapefruit juice on the pharmacokinetics of erythromycin

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Abstract

To study the effects of grapefruit juice on the pharmacokinetics of erythromycin. The effects of grapefruit juice intake on the pharmacokinetics of erythromycin were investigated in six healthy male volunteers, who received 400 mg erythromycin with either water or grapefruit juice. The measurement of erythromycin in plasma samples were achieved by simple Sep-Pak CN cartridge extraction coupled with the electrochemical determination HPLC method, which was developed for the determination of erythromycin in human plasma in the present study. Grapefruit juice, compared with water intake, significantly (P<0.05) increased the mean Cmax value (1.65+/-0.94 versus 2.51+/-0.68 microg/ml) and the mean AUC0-12 value of erythromycin (5.92+/-3.25 versus 8.80+/-1.32microg.h/ml). However, the Tmax and t1/2 values of erythromycin were not affected by grapefruit juice intake. These results indicate that the bioavailability of erythromycin was increased by the inhibitory effect of grapefruit juice on cytochrome P450 (CYP) 3A4-mediated metabolism in the small intestine.

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... В последнее время неоднократно сообщалось о влиянии грейпфрута на эффективность некоторых лекарственных средств (Kanazawa S. et al., 2001;Mahgoub A.A., 2002;Okura T. et al., 2008;Seidegård J. et al., 2009;Nieminen T.H. et al., 2010;Bailey D.G. et al., 2013�. �одобным свойством в некоторой степени облада�т и дру� �. �одобным свойством в некоторой степени облада�т и дру� гие цитрусовые: апельсины горьких сортов (Севилья�, помело и лайм (Malhotra S. et al., 2001 ...
... �ля предни� �олона получен отрицательный ре�ультат (Hollander A.A. et al., 1995�. �редставля�т интерес также в�аимодействия грейпфрута с антибиотиками: сообщалось о повышении биодоступности эритромицина под действием сока грейпфрута; для кларитроми� цина ре�ультат отрицателен (Hollander A.A. et al., 1995;Kanazawa S. et al., 2001�. Сообщалось, что грейпфрут и содержащийся в нем нарингин облада�т благоприятным действием при сахарном диабете и ожирении (Jung U.J. et al., 2004;Punithavathi V.R. et al., 2008;Mahmoud A.M. et al., 2012; Xulu S., Oroma Owira P.M., Alam M.A. et al., 2014;Chudnov�kiy R. et al., 2014;Murunga A.N. et al., 2016;Sirovina D. et al., 2016�. ...
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Full text: https://www.umj.com.ua/article/105072/vzaimodejstvie-grejpfruta-s-lekarstvennymi-preparatami Related article in English: https://www.researchgate.net/publication/319434835_Grapefruit_Some_perspectives_in_pharmacology_and_nutrition
... Kalzium-Antagonisten Amlodipin [41] Kein Diltiazem [37] Kein Felodipin [37] 1.5 bis 3.5-fach erhöht Nicardipin [37] 1.3 bis 2-fach erhöht Nifedipin [37] 1.3 bis 2-fach erhöht Nimodipin [37] 1.5-fach erhöht Nisoldipin [37] 2-fach erhöht Nitrendipin [37] 1.4 bis 2-fach erhöht Verapamil [37] 1.4-fach erhöht Statine Atorvastatin [42] 2.5-fach erhöht Pravastatin [42] Kein Simvastatin [40] 12-fach erhöht Benzodiazepine Alprazolam [56] Kein Midazolam [37,57] 1.5-fach erhöht Triazolam [37] 1.5-fach erhäht Andere Amiodaron [43] 1.5-fach erhöht Cisaprid [44,45] 1.5-fach erhöht Cyclosporin A [37] 1.5-fach erhöht Digoxin [58] Kein Ethinylestradiol [37] 1.3-fach erhöht Erythromycin [46] 1.5-fach erhöht Omeprazol [59] Kein Saquinavir [60] 2-fach erhöht Theophyllin [61] Kein ythromycin [46]. [52]. ...
... Kalzium-Antagonisten Amlodipin [41] Kein Diltiazem [37] Kein Felodipin [37] 1.5 bis 3.5-fach erhöht Nicardipin [37] 1.3 bis 2-fach erhöht Nifedipin [37] 1.3 bis 2-fach erhöht Nimodipin [37] 1.5-fach erhöht Nisoldipin [37] 2-fach erhöht Nitrendipin [37] 1.4 bis 2-fach erhöht Verapamil [37] 1.4-fach erhöht Statine Atorvastatin [42] 2.5-fach erhöht Pravastatin [42] Kein Simvastatin [40] 12-fach erhöht Benzodiazepine Alprazolam [56] Kein Midazolam [37,57] 1.5-fach erhöht Triazolam [37] 1.5-fach erhäht Andere Amiodaron [43] 1.5-fach erhöht Cisaprid [44,45] 1.5-fach erhöht Cyclosporin A [37] 1.5-fach erhöht Digoxin [58] Kein Ethinylestradiol [37] 1.3-fach erhöht Erythromycin [46] 1.5-fach erhöht Omeprazol [59] Kein Saquinavir [60] 2-fach erhöht Theophyllin [61] Kein ythromycin [46]. [52]. ...
Article
Phytotherapeutic preparations contain a large number of pharmacologically active components. Protective systems have evolved to detoxify and eliminate these xenobiotics. Among them is the cytochrome P450 system and the transporter p-glycoprotein in intestine and liver that control the absorption, biotransformation and elimination of drugs. Components of phytotherapeutic preparations can interfere with the function of these systems and lead to interactions with drugs. St John's wort, for example, induces the expression of p-glycoprotein and CYP3A4 in liver and intestine and thereby decreases the activity of other drugs. Garlic extracts as well may decrease the activity of drugs that are substrates for CYP3A4. In contrast, grapefruit juice inhibits intestinal CYP3A4. This results in a higher bioavailability of some drugs and possibly more adverse effects. Some relevant interactions were only detected after many years of widespread use, indicating that the treating physician should not only inquire about a change in co-medication but also about the use of alternative medicines or a change in dietary habits when a patient presents with unexpected and unusual adverse effects or a sudden loss of drug efficacy. It would be desirable if more information regarding the potential for interactions with commonly used drugs was available prior to registration of new phytotherapeutic preparations in order to document their safety for patients who require continuous treatment with a drug because of a chronic disease.
... 60 Kanazawa et al. revealed that grapefruit juice intake led to more than 1.5 times higher AUC and C max of erythromycin base. 61 This may be explained by a decrease in first-pass metabolism of erythromycin in the small intestine due to the inhibition of CYP3A by grapefruit juice components. Conversely, regarding telithromycin, Shi et al. did not observe significant changes in bioavailability after co-intake with grapefruit juice. ...
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Background Effective management of drug–food interactions is crucial for enhancing antibiotics’ efficacy/safety. Adhering to PRISMA guidelines, we conducted a systematic review to assess the impact of dietary interventions on the bioavailability of 15 macrolides and 10 tetracyclines. Methods We included studies examining the influence of food, beverages, antacids, and mineral supplements on the pharmacokinetic parameters of orally administered macrolides and tetracyclines. We searched Medline (via PubMed), Embase and Cochrane Library databases up to December 2022. Risk of bias was assessed using Cochrane and NIH tools. Quantitative analyses were conducted if two or more comparable food-effect studies were available; otherwise, a qualitative summary was provided. Results We included 120 studies from 97 reports. Meta-analyses were conducted for 8 macrolides and 4 tetracyclines, with qualitative synthesis for 10 and 9, respectively. About 64% of the studies were open-label, crossover designs. Our assessment found that 37% of the studies had a high risk of bias, while only 6% had low risk. Food significantly affected 10 of 13 macrolides (77%) and 6 of 7 tetracyclines (86%). High positive effects on bioavailability were seen with extended-release azithromycin and clarithromycin, and erythromycin estolate. High negative impacts were observed with erythromycin propionate and stearate, azithromycin capsules, demeclocycline and omadacycline. Antacids and mineral supplements significantly decreased tetracyclines absorption. Milk and grapefruit juice showed variable impacts on absorption. Discussion Interactions depend on antibiotics’ physicochemical characteristics, intervention type, drug formulation and potential patient factors. The quality of evidence was rated low due to outdated studies, methodological diversity and unequal data availability.
... Clinical pharmacokinetic data from human studies (13)(14)(15)(16)(17)(18) and drug monograph databases (e.g., Micromedex, FDA) were used to obtain C max (maximum plasma concentration) and f u (fraction of drug unbound in the plasma). Comparisons between unbound C max (f u *C max ) and IC 50 obtained in vitro ((f u *C max )/IC 50 > 0.1) were used to estimate the likelihood that a drug may inhibit SLC19A2 clinically (Table I) (19,20). ...
Article
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A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.
... In addition, grapefruit juice has been approved as a common dietary inhibitor of CYP3A activity in several studies. The metabolism of several clinically used drugs such as coumarin, cyclosporine, ethinylestradiol, midazolam, terfenadine, verapamil [23,24], and erythromycin [25] was inhibited by grape fruit juice [26]. Notably, orally ingested grapefruit juice does not alter the function of hepatic CYP3A4 while decreasing the small-intestinal protein levels of CYP3A4 by >60% [27]. ...
Article
Introduction: The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug-drug interactions (DDIs). Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of drug-drug interactions. It also provides a comprehensive overview and summary of the latest update in the role of PBPK modeling in prediction of intestinal metabolism and DDIs in humans. Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.
... The metabolic effect or inhibitory activity of erythromycin on CYP3A needs to be clarified, because the small intestinal CYP enzyme has been recognized as an important factor in the pharmacokinetics of drug bioavailability and drug-drug interaction. Therefore, in the present study, we examined the drug interaction between erythromycin and medicinal plants 8,9 . ...
... A secondary objective of the erythromycin DDI study was to explore the effect of a single dose of bitopertin on the pharmacokinetics of erythromycin at steady state. The erythromycin Inhibition of CYP3A4 in the small intestine increases the bioavailability of erythromycin [18]. As erythromycin is metabolized to N-desmethylerythromycin by CYP3A [19], this metabolite was measured after implementation of a protocol amendment. ...
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To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling. The effects of ketoconazole and erythromycin were assessed in two male volunteer studies with open-label, two-period, fixed-sequence designs. Twelve subjects were enrolled in each of the studies. In period 1, a single dose of bitopertin was administered; in period 2, 400 mg ketoconazole was administered once daily for 17 days or 500 mg erythromycin was administered twice daily for 21 days. A single dose of bitopertin was coadministered on day 5. Pharmacokinetic parameters were derived by non-compartmental methods. Simulated bitopertin profiles using dynamic PBPK modelling for a typical healthy volunteer in GastroPlus(®) were used to predict changes in pharmacokinetic parameters. In healthy volunteers, coadministration of ketoconazole increased the bitopertin area under the plasma concentration-time curve (AUC) from 0 to 312 h (AUC0-312h) 4.2-fold (90 % confidence interval [CI] 3.5-5.0) and erythromycin increased the AUC from time zero to infinity (AUC0-inf) 2.1-fold (90 % CI 1.9-2.3). The peak concentration (C max) increased by <25 % in both studies. Simulated bitopertin profiles using PBPK modelling showed good agreement with the observed AUC ratios in both studies. The predicted AUC0-inf ratios for the interaction with ketoconazole and erythromycin were 7.7 and 1.9, respectively. Strong CYP3A4 inhibitors increase AUC0-inf of bitopertin 7- to 8-fold and hence should not be administered concomitantly with bitopertin. Moderate CYP3A4 inhibitors double AUC0-inf.
... At the end of the 6-week-long feeding period, chickens were treated with a single intramuscular (i.m.) dose (30 mg/kgÁBW, pectoral muscle) of erythromycin (Gallimycin â ; Ceva, Libourne, France) injection. As the aim of the study was to evaluate the metabolic interaction of orally applied butyrate with concomitantly administered drugs, and feed additives may interact with oral drug utilization (Kanzawa et al., 2001), parenteral (i.m.) erythromycin application was chosen. Blood samples were collected at 0.0, 0.5, 1, 1.5, 2, 3, 4, 8, and 12 h after the injection . ...
... Buspirone 9.21 * [84] Clozapine 1.01 – mean plasma concentration ratio [85] 1.15 * – mean trough level ratio [86] 0.92 [87] Fluvoxamine Erythromycin 1.49 [97] Telithromycin 1.05 [98] Antimalarials ...
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Introduction: Since their initial discovery in 1989, grapefruit juice (GFJ)-drug interactions have received extensive interest from the scientific, medical, regulatory and lay communities. Although knowledge regarding the effects of GFJ on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited. Areas covered: This article reviews the in vitro effects of GFJ and its constituents on the activity of CYP enzymes, organic anion-transporting polypeptides (OATPs), P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported AUC ratios for available GFJ-drug interaction studies are also provided. Relevant investigations were identified by searching the PubMed electronic database from 1989 to 2010. Expert opinion: GFJ increases the bioavailability of some orally administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, GFJ can decrease the oral absorption of a few drugs that rely on OATPs in the gastrointestinal tract for their uptake. The number of drugs shown to interact with GFJ in vitro is far greater than the number of clinically relevant GFJ-drug interactions. For the majority of patients, complete avoidance of GFJ is unwarranted.
... 44 [17] [46] [47] [48] Nicardipine 15-45 0.61 12 [49] Alfentanil 42±13 [40] 0.61 10 [40] Triazolam 55-60 0.64±0.04 38 [50] [51] [52] [53] Benidipine n/a 0.63 6 [54] Nimodipine 10±4 0.67 8 [55] Erythromycin 35±25 0.67 6 [56] Amiodarone 46±22 0.67 11 [57] Prednisone 80±11 0.67 12 [58] Cyclosporine 34 0.65±0.06 74 [59] [60] [61] [62] [63] [64] Carbamazepine 75 0.71 10 [65] Verapamil 22±8 0.71±0.04 ...
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This study aims to assess utility and limitations of grapefruit juice (GFJ) interaction studies as alternative in vivo approach to estimate intestinal availability (F(G)) in comparison to the predominantly used i.v./oral method. The F(G) estimates were obtained from the ratio of AUC in the control and the GFJ group reported previously. Due to large variability in the study design, the following inclusion criteria were applied for the selection of clinical studies: no change in elimination half-life in the presence of GFJ, administration of GFJ with or up to 4 h before drug intake, and a reported significant increase in AUC in the presence of GFJ. Weighted mean F(G) values were compared to estimates from i.v./oral data. Additionally, inter-study and inter-individual variation of GFJ F(G) estimates was assessed by meta-analysis for drugs with multiple studies reported. F(G) values ranged from 0.07 to 0.92 for lovastatin and quinidine, respectively. Overall, the inter-individual variation in GFJ F(G) estimates (16-54%) was higher than the inter-study (5.7-39%) with the exception of nisoldipine and simvastatin where inter-study variations of 53-88% were observed. Weighted average GFJ F(G) estimates were comparable to i.v./oral, supporting the application of this approach as an alternative to i.v./oral data for predominantly metabolised drugs (r(2) = 0.65; n=10). In contrast, this approach is of limited use for drugs whose disposition is co-dependent on efflux/uptake transporters and metabolic enzymes. An area of high intestinal extraction (F(G) < or = 0.25) is identified as problematic, as availability of conclusive data is limited in this area.
... No food-drug interaction has been demonstrated with clarithromycin or roxithromycin. [187,193,194] Ingestion of grapefruit juice increases the bioavailability of erythromycin [195] by 49% (inhibition of first-pass metabolism) but does not affect clarithromycin. [196] ...
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Interactions between food and drugs may inadvertently reduce or increase the drug effect. The majority of clinically relevant food-drug interactions are caused by food-induced changes in the bioavailability of the drug. Since the bioavailability and clinical effect of most drugs are correlated, the bioavailability is an important pharmacokinetic effect parameter. However, in order to evaluate the clinical relevance of a food-drug interaction, the impact of food intake on the clinical effect of the drug has to be quantified as well. As a result of quality review in healthcare systems, healthcare providers are increasingly required to develop methods for identifying and preventing adverse food-drug interactions. In this review of original literature, we have tried to provide both pharmacokinetic and clinical effect parameters of clinically relevant food-drug interactions. The most important interactions are those associated with a high risk of treatment failure arising from a significantly reduced bioavailability in the fed state. Such interactions are frequently caused by chelation with components in food (as occurs with alendronic acid, clodronic acid, didanosine, etidronic acid, penicillamine and tetracycline) or dairy products (ciprofloxacin and norfloxacin), or by other direct interactions between the drug and certain food components (avitriptan, indinavir, itraconazole solution, levodopa, melphalan, mercaptopurine and perindopril). In addition, the physiological response to food intake, in particular gastric acid secretion, may reduce the bioavailability of certain drugs (ampicillin, azithromycin capsules, didanosine, erythromycin stearate or enteric coated, and isoniazid). For other drugs, concomitant food intake may result in an increase in drug bioavailability either because of a food-induced increase in drug solubility (albendazole, atovaquone, griseofulvin, isotretinoin, lovastatin, mefloquine, saquinavir and tacrolimus) or because of the secretion of gastric acid (itraconazole capsules) or bile (griseofulvin and halofantrine) in response to food intake. For most drugs, such an increase results in a desired increase in drug effect, but in others it may result in serious toxicity (halofantrine).
... Grapefruit juice, when administered together with either of the calcium antagonists nifedipine and felodipine, increases the plasma concentration of the drug (Bailey et al., 1991). The metabolism of coumarin, cyclosporine, ethinylestradiol, midazolam, terfenadine, and verapamil (for reviews, see Ameer and Weintraub, 1997;Fuhr, 1998), as well as that of saquinavir (Kupferschmidt et al., 1998;Eagling et al., 1999) and erythromycin (Kanazawa et al., 2001), was also shown to be decreased by grapefruit juice. ...
Article
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The mammalian small intestine serves principally as the site for absorption of nutrients, water, and both beneficial and potentially harmful xenobiotics. However, it has become apparent over the past 20 years, and most notably during the past 10 years, that an array of metabolic machinery is also
... In human liver, CYP3A4 is the most abundant P450 (Waxman, 1999) and is responsible for metabolizing the largest portion of therapeutic drugs (Evans and Relling, 1999 ). There is a wide range of substrates known for CYP3A metabolism (Guengerich, 1999), including erythromycin (Kanazawa et al., 2001), cyclosporin (Nguyen et al., 1999), warfarin (Kaminsky and Zhang, 1997), 17b-estradiol (Lee et al., 2001), and numerous other therapeutic drugs. The CYP3A subfamily is a member of Clan 3, which includes the CYP3 and CYP5 families (Nelson et al., 2004). ...
Article
An analysis of the cytochrome P450 3A subfamily (CYP3A) was undertaken in order to define relationships across species among subfamily members. Some members were excluded due to incomplete sequences, while others were held in abeyance because of their almost complete homology. This is the first publication of five chimpanzee CYP3A genes-CYP3A4, CYP3A5, CYP3A7, CYP3A43, and CYP3A67. This project utilized two approaches for characterizing possible relationships-phylogenetic analysis and genomic structure. For the phylogenetic analysis, both nucleotide and amino acid sequences were aligned in silico using the CLUSTAL algorithm, and then visually inspected for accuracy. Three different computer software packages were utilized: MEGA 2.1, TREECON 1.3b, and PHYLIP 3.5. Multiple methods were used: neighbor-joining (NJ), minimum evolution (ME), maximum parsimony (MP), and maximum likelihood (ML). The resulting topologies were compared against each other to define the consensus topology. In addition, the chimpanzee, human, mouse, and rat genome databases were searched for intron/exon information pertaining to the included genes. Both methods suggest the same conclusion, defining orthologs is plausible between similar species (i.e., mouse and rat), but is less useful between species of different orders (i.e., primate and rodent) or classes (i.e., mammal and avian).
... After a single dose of erythromycin (400 mg/kg) a C max value of 2.5 g/ml (3.4 M) was obtained (Kanazawa et al., 2001). Comparing plasma concentration and the IC 50 value for erythromycin in the clinically relevant drug-drug interactions of the present study seems unlikely. ...
Article
In the present study, the involvement of cytochrome P450 enzyme(s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent KM in the range of 0.09 to 1.9 mM and Vmax from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6beta-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r2 = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism. Furthermore, in incubations with recombinant CYP3A4, all the primary metabolites were formed. In vitro interaction studies with CYP3A4 substrates and possible concomitant medication demonstrated that laquinimod inhibits the metabolism of ethinyl estradiol with an IC50 value of about 150 microM, which is high above the plasma level of laquinimod after clinically relevant doses. Ketoconazole, troleandomycin, erythromycin, prednisolone, and ethinyl estradiol inhibited the metabolism of laquinimod, and IC50 values of 0.2, 11, 24, 87, and 235 microM, respectively, were calculated. In conclusion, the present study demonstrates that laquinimod is a low affinity substrate for CYP3A4 in human liver microsomes. The likelihood for in vivo effects of laquinimod on the metabolism of other CYP3A4 substrates is minor. However, inhibitory effects on the metabolism of laquinimod by potent and specific inhibitors of CYP3A4, such as ketoconazole, are anticipated and should be considered in the continued clinical program for laquinimod.
... 24 However, single-dose, double-strength grapefruit juice caused a somewhat significant increase in exposure to erythromycin: both C max and AUC 0-12 were increased more than 1.5-fold (p<0.01 and p<0.05, respectively) with grapefruit juice. 25 With erythromycin, the magnitude of response to grapefruit juice is associated with baseline intestinal CYP3A4 activity. Subjects with low intestinal CYP3A4 activity, who therefore had a relatively high erythromycin AUC with water (> 7 mg/L•hr), were not greatly affected by grapefruit juice because they had little intestinal CYP3A4 activity to inhibit. ...
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To determine whether coadministration of the cytochrome P450 3A4 (CYP3A4) inhibitors itraconazole or grapefruit juice will modify the pharmacokinetic profile of telithromycin, and to assess the safety of telithromycin. Two single-center, open-label studies; the itraconazole study was nonrandomized, sequential, and multiple dose, and the grapefruit juice study was randomized, two-period crossover, and single dose. Two clinical investigative centers in the United States. Thirty-four healthy, nonsmoking male volunteers aged 18-45 years. All patients received telithromycin 800 mg/day; 18 patients received concomitant itraconazole 200 mg/day, and 16 received concomitant single-dose, single-strength grapefruit juice. Standard pharmacokinetic and safety measurements were performed. Itraconazole given concomitantly with telithromycin increased the steady-state area under the plasma concentration-time curve from 0-24 hours of telithromycin by 53.8% (p<0.0001). Coadministration of grapefruit juice did not affect telithromycin pharmacokinetic parameters, and telithromycin was well tolerated in both studies. Only modest changes in the pharmacokinetics of telithromycin were seen with concomitant administration of itraconazole. Telithromycin pharmacokinetics were unaffected by concomitant administration of grapefruit juice.
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Grapefruit is a citrus fruit that belongs to the Rutaceae family. One large grapefruit yields around 200–250 ml of juice, consumed regularly by many individuals owing to its nutritional value, including fiber, vitamin C, and antioxidants. Grapefruit juice (GFJ) compounds, mainly naringin, bergamottin, and 6,7-dihydroxybergamottin (DHB), inhibit intestinal CYP3A4 enzymes, which are mediated by the metabolic processes of many drugs and result in the interaction between GFJ and drugs that are CYP3A4 substrates when administered concomitantly. GFJ-drug interaction is affected by several factors, including oral bioavailability, patient vulnerability, and factors related to GFJ consumption, such as the amount of GFJ consumed and the interval between GFJ and drug administration. Many drugs from different classes have the potential for interaction, including calcium channel blockers such as felodipine, statins such as simvastatin, immunosuppressants, benzodiazepines such as midazolam, antihistamines such as terfenadine, and many other drugs. Pharmacists have a strong medical background that makes them able to predict grapefruit-drug interactions. Thus, they play a critical role in reducing the risk of GFJ-drug interactions by advising and educating patients when dispensing prescribed and Over-the-counter (OTC) drugs.
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Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in the stomach and small intestine, GI transit of water and dosage forms, and microbiota. Additionally, case examples of food effects on GI physiology and subsequent changes in oral drug absorption are provided. Furthermore, the effects of food, especially fruit juices (e.g., grapefruit, orange, apple) and green tea, on transporter-mediated permeation and enzyme-catalyzed metabolism of drugs in intestinal epithelial cells are also summarized comprehensively.
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Infections caused by Staphylococcus aureus are a serious global threat, and with the emergence of antibiotic resistance, even more difficult to treat. One of the possible complications in antistaphylococcal therapy represents negative interactions of antibiotics with food. In this study, the in vitro interaction between oxacillin and crude palm seed oil from Astrocaryum vulgare , Cocos nucifera , and Elaeis guineensis against nine strains of S. aureus was determined using the checkerboard method. Lauric acid was identified as a major constituent of all tested oils by gas chromatography. The results showed strong concentration dependent antagonistic interactions between palm oils and oxacillin with values of fractional inhibitory concentrations indices ranging from 4.02 to 8.56 at concentrations equal or higher than 1024 µg/mL of the tested oils. Similarly, lauric acid in combination with oxacillin produced antagonistic action with fractional inhibitory concentration indices ranging from 4.01 to 4.28 at 1024 µg/mL. These findings suggest that interference between oxacillin and palm oils and their constituents can negatively affect the treatment of staphylococcal infections in humans and other animals.
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Self-medication, according to the World Health Organization, is the choice and use of medicines by people to treat self-recognized sicknesses or symptoms and is one part of self-care (1). It is the treatment of common health problems with products specifically designed and labeled to be used without medical supervision and approved as safe and effective for such use. Medicines for self-medication are typically known as ënon-prescriptioní or ëover the counterí preparations (OTC) and they are available without a doctorís prescription through pharmacies. The term OTC (over-the-counter) should be understood as taking medicines issued without a doctorís prescription. The decision on their use is made by the patient, possibly after consultation with the pharmacist. Products with the status of dietary supplements do not show pharmacological effect but only physiological effect. According to the official definition, they are a concentrated source of mineral components or other nutritional substances having a physiological or nutritional effect, whose task is to enrich the daily diet with components whose insufficient amount is supplied in the meals taken.
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Drug–food interactions can be detrimental to the pharmacologic treatment of infectious diseases by decreasing the efficacy or increasing the toxicity of antimicrobials. Compared to well-known drug–drug interactions, drug–food interactions often go unrecognized and can lead to poor clinical outcomes. In addition to affecting the risk–benefit ratio of the antimicrobial, drug–food interactions can be cumbersome to patients and lead to nonadherence due to interference with daily activities. This chapter will discuss the mechanisms of drug–food interaction, the appropriate methodology for food-effect studies, the specific effects of food on a variety of antimicrobials, as well as the recommended dosing guidelines for administration with regard to meals.
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Solithromycin, a ketolide/macrolide antibiotic, has recently been reported to be free of the expected QT-prolonging effect of macrolides. It appears that its keto substitution provides a structural basis for this observation, as the other two tested ketolides also have minimal QT effect. Among non-cardiovascular therapies, antimicrobials probably carry the greatest potential to cause cardiac arrhythmias. This is a result of their propensity to bind to the delayed rectifier potassium channel, IKr, inducing QT prolongation and risk of torsades de pointes ventricular tachycardia, their frequent interference with the metabolism of other QT prolongers and their susceptibility to metabolic inhibition by numerous commonly used drugs. Unfortunately, there is evidence that medical practitioners do not take account of the QT/arrhythmia risk of antimicrobials in their prescribing practices. Education on this topic is sorely needed. When a macrolide is indicated, a ketolide should be considered in patients with a QT risk.
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Oral administration is the most commonly used route for drug treatment. Intestinal cytochrome P450 (CYP)-mediated metabolism can eliminate a large proportion of some orally administered drugs before they reach systemic circulation, while leaving the passage of other drugs unimpeded. A better understanding of the ability of intestinal P450 enzymes to metabolize various clinical drugs in both humans and preclinical animal species, including the identification of the CYP enzymes expressed, their regulation, and the relative importance of intestinal metabolism compared to hepatic metabolism, is important for improving bioavailability of current drugs and new drugs in development. Here, we briefly review the expression of drug-metabolizing P450 enzymes in the small intestine of humans and several preclinical animal species, and provide an update of the various factors or events that regulate intestinal P450 expression, including a cross talk between the liver and the intestine. We further compare various clinical and preclinical approaches for assessing the impact of intestinal drug metabolism on bioavailability, and discuss the utility of the intestinal epithelium–specific NADPH-cytochrome P450 reductase-null (IECN) mouse as a useful model for studying in vivo roles of intestinal P450 in the disposition of orally administered drugs.
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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.
Article
Butyrate, a commonly applied feed additive in poultry nutrition, can modify the expression of certain genes, including those encoding cytochrome P450 (CYP) enzymes. In comparative in vitro and in vivo experiments, the effect of butyrate on hepatic CYP genes was examined in primary cultures of chicken hepatocytes and in liver samples of chickens collected from animals that had been given butyrate as a feed additive. Moreover, the effect of butyrate on the biotransformation of erythromycin, a marker substance for the activity of enzymes of the CYP3A family, was investigated in vitro and in vivo. Butyrate increased the expression of the avian-specific CYP2H1 both in vitro and in vivo. In contrast, the avian CYP3A37 expression was decreased in hepatocytes following butyrate exposure, but not in the in vivo model. CYP1A was suppressed by butyrate in the in vitro experiments, and overexpressed in vivo in butyrate-fed animals. The concomitant incubation of hepatocytes with butyrate and erythromycin led to an increased CYP2H1 expression and a less pronounced inhibition of CYP3A37. In in vivo pharmacokinetic experiments, butyrate-fed animals given a single i.m. injection of erythromycin, a slower absorption phase (longer Thalf-abs and delayed Tmax) but a rapid elimination phase of this marker substrate was observed. Although these measurable differences were detected in the pharmacokinetics of erythromycin, it is unlikely that a concomitant application of sodium butyrate with erythromycin or other CYP substrates will cause clinically significant feed-drug interaction in chickens.
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Introduction Transporter Classification, Localization, and Functions Clinical Drug-Drug Interactions Polymorphisms and Regulation of Drug Transporters In Vitro Methods in Evaluation of Drug Transporters Transporters-Drug-Metabolizing Enzymes Interplay Outlook References
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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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Drug–food interactions can be a major source of patient inconvenience and nonadherence through disruptions in a patient’s daily schedule. Lack of knowledge of potentially significant drug–food interactions can lead to poor clinical outcomes. For example, administering ketoconazole tablets with a meal may decrease absorption. In contrast, each dose of posaconazole oral suspension should be administered with a full meal or liquid nutritional supplement for optimal absorption. Hence, the components of food may interact directly with medications. Different formulation of a drug also affect the magnitude of drug-food interactions. A number of dietary factors, such as dietary protein, cruciferous vegetables, and charcoal-broiled beef are known to have potential for altering metabolism of drugs. This chapter will describe mechanisms of drug–food interactions and U.S. Food and Drug Administration (FDA) guidelines for drug–food interaction studies as well as pharmacokinetic parameters affected by food.
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Drug-food interactions can be a major source of patient inconvenience and nonadherence through disruptions in a patient’s daily schedule. Unless advised to the contrary, patients often take drugs with meals as a suitable adherence reminder and to lessen gastrointestinal (GI) side effects. Lack of knowledge of potentially significant drug-food interactions can lead to poor clinical outcomes. This chapter describes mechanisms of drug-food interactions and US Food and Drug Administration (FDA) guidelines for drug-food interaction studies. Antimicrobial drug-food interactions based on drug classes and pharmacokinetics are described, as are the recommended dosing guidelines. In addition, anti-infectives and the disulfiramlike reaction and two case studies are included.
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The first report of grapefruit juice (GFJ) interacting with a drug, altering its bioavailability, was published in 1991. This accidental discovery was made in a study on ethanol-drug interactions-the bioavailability of felodipine was increased when subjects were consuming GFJ concomitantly with felodipine, associated with a lower dehydrofelodipine/felodipine area under the curve (AUC) ratio, decreased diastolic blood pressure, and an increased heart rate (1). Subsequent research in the area of fruit-drug interactions focused on grapefruit and grapefruit compounds of which several were found to affect the absorption or metabolism of certain drugs. GFJ was shown to alter the pharmacokinetics of several drugs such as statins, calcium channel blockers, antibiotics, and others (1-8). Other fruits, vegetables, and dietary supplements also have the potential to cause an adverse interaction with conventional drugs (9). Over 16% of all prescription drug users reported that they concurrently use at least one plant-based dietary supplement, including grapefruit and citrus products (10).
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Tacrolimus is a well-known potent immunosuppressant agent, which has various drug-drug or food-drug interactions. Previously, we found a renal transplant recipient who increased tacrolimus blood concentrations after ingestion of pomelo as a rare case. So, we investigated the effect of pomelo after its administration for one day or 3 consecutive days on the pharmacokinetics of tacrolimus in rats. We also confirmed the effects of grapefruit, turmeric, and ginger. The tacrolimus blood concentrations of the rats pre-treated with 100% pomelo juice were significantly higher than those pre-treated with water. On the other hand, the tacrolimus blood concentrations of the rats pre-treated with 50% pomelo juice were not significantly different from those pre-treated with water. The pomelo-tacrolimus interaction showed concentration dependency. Even low concentration of pomelo juice could enhance the blood concentrations of tacrolimus by repeated administration. The inhibitory effect of 100% pomelo juice disappeared 3 days after intake. The AUC values of tacrolimus in the rats pre-treated with grapefruit juice, ginger juice, and turmeric juice were significantly larger than those pre-treated with water. We could confirm the pomelo-tacrolimus interaction, which we discovered in a case study, quantitatively. We newly found the influence of turmeric and ginger on tacrolimus pharmacokinetics, comparable to pomelo.
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Introduction: The concentration of many orally given medications may be affected by grapefruit or grapefruit juice consumption. It may result in numerous harmful effects. Interaction of grapefruit with drugs: Taking only one cup of juice may induce interactions with different drugs even during the period of a few days. The effect is induced by suppression of cytochrome P450 isoenzyme CYP3A4 in the intestinal wall. The Latin name of grapefruit, Citrus paradisi, is quite opposite to the effects which could be induced by taking grapefruit and some medications at the same time. It is necessary to avoid taking grapefruit with the drugs whose pharmacokinetics could be altered by the active principles found in that fruit. Discussion: The coloured grapefruit contains less furanocoumarins, but there is no difference in induction and intensity of pharmacokinetic interaction with drugs related to its colour. Other citrus fruits (orange, lemon) do not have such effects, but some other fruits (pomegranate, stella fruit, banpeiyu, hassaku, takaoka-buntan and kinkan) exert inhibitory effects on the activity of cytochrome P450 isoenzyme.
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Introduction. The concentration of many orally given medications may be affected by grapefruit or grapefruit juice consumption. It may result in numerous harmful effects. Interaction of grapefruit with drugs. Taking only one cup of juice may induce interactions with different drugs even during the period of a few days. The effect is induced by suppression of cytochrome P450 isoenzyme CYP3A4 in the intestinal wall. The Latin name of grapefruit, Citrus paradisi, is quite opposite to the effects which could be induced by taking grapefruit and some medications at the same time. It is necessary to avoid taking grapefruit with the drugs whose pharmacokinetics could be altered by the active principles found in that fruit. Discussion. The coloured grapefruit contains less furanocoumarins, but there is no difference in induction and intensity of pharmacokinetic interaction with drugs related to its colour. Other citrus fruits (orange, lemon) do not have such effects, but some other fruits (pomegranate, stella fruit, banpeiyu, hassaku, takaoka-buntan and kinkan) exert inhibitory effects on the activity of cytochrome P450 isoenzyme.
Article
Grapefruit juice and grapefruit product consumption have potential health benefits; however, their intake is also associated with interactions with certain drugs, including calcium channel blockers, immunosuppressants and antihistamines. The primary mechanism through which interactions are mediated is mechanism-based intestinal cytochrome P450 3A4 inhibition by furanocoumarins resulting in increased bioavailability of administered medications that are substrates. Grapefruit products have also been associated with interactions with P-glycoprotein (P-gp) and uptake transporters (e.g. organic anion-transporting polypeptides [OATPs]). Polyphenolic compounds such as flavonoids have been proposed as the causative agents of the P-gp and OATP interactions. The mechanisms and magnitudes of the interactions can be influenced by the concentrations of furanocoumarins and flavonoids in the grapefruit product, the volume of juice consumed, and the inherent variability of specific enzymes and transporter components in humans. It is therefore challenging to predict the extent of grapefruit product-drug interactions and to compare available in vitro and in vivo data. The clinical significance of such interactions also depends on the disposition and toxicity profile of the drug being administered. The aim of this review is to outline the mechanisms of grapefruit-drug interactions and present a comprehensive summary of those agents affected and whether they are likely to be of clinical relevance.
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Substitution of branded medicine with a generic equivalent is already common. Robin Ferner, Warren Lenney, and John Marriott argue that concerns about UK plans to let pharmacists make the decision are unwarranted
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To evaluate the pharmacokinetics and adverse effects of medicinal herbs, as well as clinical evidence of herb-drug interactions. Electronic searches were conducted in multiple databases, including MEDLINE, EMBASE, the Cochrane Library, CINAHL, NAPRALERT, International Pharmaceutical Abstracts, CANCERLIT, CISCOM, and HerbMed. Search terms used included common names, scientific names, and synonyms for the herbs and their primary active constituents. Bibliographies of relevant articles were also searched by hand to obtain additional references. No restrictions were placed on language or quality of publications. All literature collected pertained to adverse effects, pharmacokinetics, and suspected or confirmed cases of herb-drug interactions. Over 80 herbs or botanicals (including plants, fungi, algae, and common constituents) were identified that had clinically significant interactions with prescription and over-the-counter drugs. Interestingly, herbs beginning with the letter "g" (garlic, ginger, ginkgo, and grapefruit) were among the herbs most commonly involved in herb-drug interactions. Drugs with anticoagulant/antiplatelet activity (e.g. warfarin, aspirin) were frequently implicated in herb-drug interactions, with documented interactions with over 30 herbs and herbal products. Because many herbs have demonstrated adverse effects on the liver, the potential for interaction with hepatotoxic agents (such as acetaminophen) is also significant. Clinical outcomes of reported herb-drug interactions ranged from mild to severe. Of note, fatalities (though rare) have occurred with concomitant ephedra and caffeine use. As herbal products (and dietary supplements in general) continue to grow in popularity, patients and health care providers should be vigilant of potential herb-drug interactions.
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The impact of food on the pharmacokinetics of a drug has important implications in drug development. This commentary is aimed at addressing two key challenges, developability of drugs whose pharmacokinetics are severely influenced by food, and the need for addressing the effects of fruit juice ingredients which modulate metabolic/efflux properties of a compound. Perspectives on the value in predicting food-drug interactions during preclinical development, timing of clinical food-drug interaction studies, and implications of food effects are presented herein.
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Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.
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A standardized extract of Citrullus colocynthis used as an oral natural laxative in folk medicine was tested for its influence on liver function parameters in vitro. Cytochrome P450 (CYP) dependent production of reactive oxygen species (ROS) under the influence of Citrullus colocynthis extract was investigated by means of stimulated lipid peroxidation (LPO), H2O2 formation and amplified chemiluminescence in rat liver microsomes. In rat liver 9000 x g supernatants 4 monooxygenase reactions mediated by different CYP forms were measured. Putative hepatotoxic effects of Citrullus colocynthis extract were measured by means of potassium and GSH concentrations in and LDH leakage from precision-cut rat liver slices. For possible hepatoprotective effects the influence of the extract on carbon tetrachloride-induced changes of these parameters was investigated. Citrullus colocynthis extract in concentrations higher than 10 microg/ml incubation mixture proved to inhibit lipid peroxidation and ROS-production as well as CYP1A-, 2B- and 3A-dependent reactions with typical substrates. In contrast, H2O2 production was not reduced under the influence of the extract, a slight but significant increase was seen. Citrullus colocynthis extract was found to be free of hepatotoxic effects in concentrations up to 100 microg/ml incubation mixture when liver slices were incubated in William's medium E for 22 hours. All viability parameters used were not influenced by the extract of Citrullus colocynthis. Carbon tetrachloride induced hepatotoxicity could not be prevented or alleviated. Moreover, the damage was sometimes enhanced by higher extract concentrations.
Article
Changes in dietary habits favouring diets rich in fruits and vegetables, and a meteoric rise in the consumption of dietary supplements and herbal products have substantially increased human exposure to phytochemicals. It is, therefore, not surprising that diet and herbal remedies can modulate drug-metabolising enzyme systems, such as cytochromes P450, leading to clinically relevant drug-phytochemical interactions. Phytochemicals have the potential to both elevate and suppress cytochrome P450 activity. Such effects are more likely to occur in the intestine, where high concentrations of phytochemicals may be achieved, and alteration in cytochrome P450 activity will influence, in particular, the fate of drugs that are subject to extensive first-pass metabolism as a result of intestinal cytochrome P450-mediated biotransformation. Moreover, it is becoming increasingly apparent that phytochemicals can also influence the pharmacological activity of drugs by modifying their absorption characteristics through interaction with drug transporters. Clearly, phytochemicals have the potential to alter the effectiveness of drugs, either impairing or exaggerating their pharmacological activity.
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It is well known that intake of grapefruit juice affects the pharmacokinetics of various kinds of drugs. It has been reported that other citrus juices also interact with certain drugs. To re-evaluate citrus juice-drug interactions based on currently available evidence, a literature search was conducted for new and updated information since the grapefruit juice-drug interaction was last reviewed in 1998. MEDLINE (1998-October 2004) was accessed and more than 200 reports were found. The effects of grapefruit juice ingestion on the pharmacokinetics of orally administered drugs have been reported for 40 drugs since the reviews published in 1998. Increases in either area under the concentration-time curve (AUC) or maximum plasma concentration (C(max)) were found with 34 of these, the major mechanism being considered to be inactivation of intestinal cytochrome P450 3A4, a so-called mechanism-based inhibition. Although recent reports point to the inhibitory effects of grapefruit juice on the function of P-glycoprotein, which transports substrates from enterocytes back into the lumen, the contribution to the bioavailability of drugs that are substrates of P-glycoprotein has not been established yet. Dramatic decreases in AUC and C(max) for two drugs in association with grapefruit juice ingestion has been reported and, in these cases, inhibitory effects on organic anion transporting polypeptide, which mediates absorption from the intestinal lumen to enterocytes, might be involved. Other citrus juices such as Seville (sour) orange juice and commonly ingested varieties of orange juice also showed significant effects on the AUC and C(max) of some drugs. Although the situation is complex and uncertainties remain, we recommend that patients avoid citrus juice intake while taking medications and that healthcare providers advise against citrus juice intake in this setting until any interactions with subject drugs can be clarified in clinical studies.
Article
Naringin, a grapefruit constituent interacts with many medications including caffeine, a popular weight loss supplement. The purpose of the current study was to identify changes in caffeine pharmacokinetics, resting energy expenditure (REE), oxygen consumption (VO 2 ) and respiratory exchange ratio (RER) after an acute dosage of caffeine and naringin. Using a double‐blinded, counterbalanced design, REE, VO 2 , and RER were measured before and systematically for 8 h after a single dosage of caffeine (CAF, 200 mg) with and without naringin (100 mg (CN100) or 200 mg (CN200)) in 10 apparently healthy individuals. A standardized meal was provided following 240‐minute measurements (400 kcals; 35 g carbohydrate; 27 g protein; 7 g fat). Caffeine, CN100, CN200 did not alter VO 2 or VO 2 area under the curve (137 301 ± 8318, 139 729 ± 9300, 134 297 ± 8318, mL/480 min). Resting energy expenditure (k/cals) was 10.0 ± 1.4% higher with CAF versus CN200 (6.0 ± 1.4%) and CN100 (6 ± 1.5%) at 240 min ( P = 0.07) which was then negated following a standardized meal. Percent change in RER from pre to 240 min and pre to 480 min was not different between the CAF, CN100, or CN200 (–0.2 ± 1.7%, 1.7 ± 1.7%, –2.8 ± 1.9%). Although caffeine alone suggests a trend of increased REE, the results of the present study indicate that concurrent consumption of caffeine with naringin in acute dosages does not affect RER, VO 2 , and prevents the increase of REE in adult humans. The results suggest that the interaction of grapefruit juice and caffeine may be due to constituents of grapefruit juice other than naringin or in addition to naringin.
Article
Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and grapefruit and grapefruit juice. Several drugs interacting with grapefruit are known in different drug classes, such as HMG-CoA reductase inhibitors, calcium antagonists, and immunosuppressives. Currently known mechanisms of interaction include the inhibition of cytochrome P450 as a major mechanism, but potential interactions with P-glycoprotein and organic anion transporters have also been reported. This review is designed to provide a comprehensive summary of underlying mechanisms of interaction and human clinical trials performed in the area of grapefruit drug interactions and to point out possible replacements for drugs with a high potential for interactions.
Article
Concomitant administration of grapefruit juice can increase the plasma concentration of numerous drugs in humans and decrease the concentration of a few others. Such elevations of drug plasma concentrations have, on occasion, resulted in adverse clinical effects. Increased concentrations are primarily mediated by chemicals in grapefruit juice, which inhibit the CYP 3A4 drug-metabolizing enzyme in the small intestines. This inhibition decreases the first-pass metabolism of drugs using the CYP 3A4 intestinal system and increases the bioavailability and maximal plasma drug concentrations (Cmax) of the CYP 3A4 substrates. The effect of grapefruit juice on drug metabolism is most pronounced in drugs with a high first-pass metabolism (eg, felodipine, amiodarone), in which it inhibits the first-pass metabolism of the CYP 3A4 substrates leading to an increase in Cmax and area under the concentration time curve (AUC). The use of grapefruit juice with a few specific drugs (eg, fexofenadine, digoxin) may lower plasma drug concentrations by inhibiting drug absorption catalyzed by the organic anion transporting polypeptide (OATP).
Article
Drug-drug interactions (DDIs) caused by direct chemical inhibition of key drug-metabolizing cytochrome P450 enzymes by a co-administered drug have been well documented and well understood. However, many other well-documented DDIs cannot be so readily explained. Recent investigations into drug and other xenobiotic-mediated expression changes of P450 genes have broadened our understanding of drug metabolism and DDI. In order to gain additional information on DDI, we have integrated existing information on drugs that are substrates, inhibitors, or inducers of important drug-metabolizing P450s with new data on drug-mediated expression changes of the same set of cytochrome P450s from a large-scale microarray gene expression database of drug-treated rat tissues. Existing information on substrates and inhibitors has been updated and reorganized into drug-cytochrome P450 matrices in order to facilitate comparative analysis of new information on inducers and suppressors. When examined at the gene expression level, a total of 119 currently marketed drugs from 265 examined were found to be cytochrome P450 inducers, and 83 were found to be suppressors. The value of this new information is illustrated with a more detailed examination of the DDI between PPARalpha agonists and HMG-CoA reductase inhibitors. This paper proposes that the well-documented, but poorly understood, increase in incidence of rhabdomyolysis when a PPARalpha agonist is co-administered with a HMG-CoA reductase inhibitor is at least in part the result of PPARalpha-induced general suppression of drug metabolism enzymes in liver. The authors believe this type of information will provide insights to other poorly understood DDI questions and stimulate further laboratory and clinical investigations on xenobiotic-mediated induction and suppression of drug metabolism.
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A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small, physicochemically diverse set of 24 drug compounds. Factors such as structural diversity, commercial availability, price, and a suitable analytical technique for quantification were considered in the selection. Lipophilicity, pKa, solubility, and permeability across human Caco-2 cell monolayers were measured for the compiled data set. The results show that, by use of a physicochemically diverse data set, experimental responses over a wide range were obtained. The paper also shows how experimental difficulties due to the diversity of the data set can be overcome. We anticipate that this data set can serve as a benchmark set for validation of new experimental techniques or in silico models. It can also be used as a diverse starting data set for the development of new computational models.
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Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pre-treatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration–time curve after oral intake more than four times (p <0.001) and reduced clearance of intravenously administered midazolam by 54% (p <0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p <0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.
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Terfenadine is a nonsedating H1-antagonist that when overdosed, used with hepatic compromise, or when given with ketoconazole results in accumulation of parent terfenadine, prolongation of the QT interval, and torsades de pointes in susceptible patients. Nine subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral erythromycin (500 mg every 8 hours). All subjects increased metabolite concentrations after the addition of erythromycin for 1 week. The maximum concentration of metabolite increased by a mean of 107% and the mean metabolite area under the concentration-time curve increased by 170%. Three subjects accumulated unmetabolized terfenadine after administration of erythromycin for 1 week. Electrocardiographic data revealed changes in QT intervals and ST-U complexes in a subset of subjects who accumulated terfenadine. We conclude that erythromycin alters the metabolism of terfenadine, leading to accumulation of terfenadine in certain individuals that is associated with altered cardiac repolarization.
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The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring. Josamycin, midecamycin and probably also the related compounds miocamycin, clarithromycin and flurithromycin, may have a clinically significant interaction with carbamazepine and cyclosporin, requiring close monitoring. Roxithromycin interaction with drugs such as theophylline or cyclosporin does not seem to justify a dosage reduction. No pharmacokinetic interactions have yet been described for spiramycin, rokitamycin, dirithromycin and azithromycin.
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Some drugs demonstrate a significantly greater (up to 3-fold) mean oral bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompanied by altered drug action. Study design factors possibly contribute to the magnitude of changes in drug bioavailability; they include the source of the citrus, its intake schedule, drug formulations and individual metabolising capacity. The components of citrus juice that are responsible for clinical drug interactions have yet to be fully determined. Based on the flavonoid naringin’s unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enzymes, naringin is likely to be one of the grapefruit components influencing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interaction studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably the inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3A substrates support the mechanistic hypothesis that 1 or more grapefruit juice components inhibit CYP3A enzymes in the gastrointestinal tract. The evaluation of the need to avoid the concomitant intake of grapefruit products with drugs is best done on an individual drug basis rather than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recipients, its interaction with grapefruit juice is likely to be clinically significant.
Article
The effect of grapefruit juice on the disposition of nicardipine after administration of intravenous and oral doses to healthy male subjects was examined. Subjects received intravenous doses (2mg/subjects) and oral doses (40mg/subjects) after 30minutes of taking 300ml of grapefruit juice or 300ml of water. Blood samples were collected for 4hours (intravenous) and 8hours (oral) period, and plasma concentrations of (+)-nicardipine and (-)-nicardipine were measured with use of the stereoselective high-performance liquid chromatography method. The pharmacokinetic parameter of intravenous nicardipine was not affected with grapefruit juice. After oral administration, grapefruit juice significantly increased maximum concentration against water ((+)-160.9, (-)-68.7 versus (+)-200.2, (-)-105.3ng/ml) and area under the curve ((+)-357,(-)-148 versus (+)-480,(-)-291ng-hr/ml) , however had not affected on elimination half-life. The difference between intravenous and oral pharmacokinetic parameter of enantiomers seem to be ascribed to stereoselective distinction in intestinal metabolism or absorption.
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 the single dose-response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements.Methods Twelve healthy males received 250 ml water or regular- or double-strength grapefruit juice with 60 mg terfenadine in a randomized crossover trial. Plasma concentrations of the cardiotoxic agent terfenadine and the active antihistaminic metabolite terfenadine carboxylate were determined over 8 hours. The QTc interval was monitored.ResultsTerfenadine concentrations were measurable (> 1 ng/ml) in 27 (20%; p < 0.001) and 39 (30%; p < 0.001) samples from individuals treated with regular- and double-strength grapefruit juice, respectively, compared to only four (3%) samples with water. Terfenadine plasma peak drug concentration (Cmax) was also higher. Terfenadine carboxylate area under the plasma drug concentration-time curve (AUC), Cmax, and time to reach Cmax (tmax) were increased by both strengths of juice. However, terfenadine carboxylate apparent elimination half-life (t½) was not altered. The magnitude of the interaction of terfenadine carboxylate AUC and Cmax ranged severalfold and correlated among individuals for regular-strength (r2 = 0.87; p < 0.0001) and double-strength (r2 = 0.78; p < 0.0001) grapefruit juice. No differences in the pharmacokinetics of terfenadine and terfenadine carboxylate were observed between the two strengths of grapefruit juice. QTc interval was not altered.ConclusionsA normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine.Clinical Pharmacology & Therapeutics (1997) 61, 401-409; doi:
Article
Background Macrolide antimicrobial agents may impair hepatic clearance of drugs metabolized by cytochrome P4503A isoforms. Potential interactions of triazolam, a substrate metabolized almost entirely by cytochrome P4503A in humans, with 3 commonly prescribed macrolides were identified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled clinical study.Methods In an in vitro model using human liver microsomes, 250 μmol/L triazolam was incubated with ascending concentrations (0 to 250 μmol/L) of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo.ResultsMean 50% inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 μmol/L troleandomycin, 27.3 μmol/L erythromycin, 25.2 μmol/L clarithromycin, and greater than 250 μmol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials.Conclusion The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.Clinical Pharmacology & Therapeutics (1998) 64, 278-285; doi:
Article
Objective To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo.Method Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersøgelser side effect rating scale.ResultsErythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 ± 43 versus 322 ± 49 ng · hr/ml from 0 to 48 hours and 229 ± 52 versus 566 ± 161 ng · hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 ± 0.31 versus 0.41 ± 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 ± 4.5 versus 40.3 ± 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases.Conclusion This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.Clinical Pharmacology & Therapeutics (1996) 59, 514-519; doi:
Article
The effect of cytochrome P-450 3A (CYP3A) substrates (erythromycin, midazolam) and an inhibitor (ketoconazole) on P-glycoprotein-mediated transport was studied in Caco-2, the human colon adenocarcinoma cell line expressing various functions of differentiated intestinal epithelial cells. The involvement of P-glycoprotein in the transport of these drugs was also examined. The basal-to-apical transport of rhodamine 123, a P-glycoprotein substrate, was inhibited by erythromycin, midazolam and ketoconazole, as well as by P-glycoprotein inhibitors such as verapamil. The apical-to-basal transport of rhodamine 123 was increased by these drugs. The transepithelial transport of erythromycin and midazolam, but not of ketoconazole, was much greater from the basal to apical side than from the apical to basal side. The inhibitory effect of verapamil was observed on the basal to apical transport of erythromycin, but not on midazolam and ketoconazole transport. In conclusion, erythromycin, midazolam and ketoconazole could interact with P-glycoprotein-mediated transport, and P-glycoprotein could be, at least in part, involved in the transport of erythromycin, but not of midazolam and ketoconazole, in the intestinal epithelia.
Article
A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 μl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1–20.0 μg/ml for plasma and 0.5–100.0 μg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.
Article
The effect of hydrochloric acid at pH 1.2-3.2 ON ERYTHROMYCIN STEARATE AND COMMERCIAL DOSAGE FORMS OF ERYTHROMYCIN STEARATE WAS STUDIED. Under all conditions examined, erythromycin was readily dissolved from the stearate as hydrochloride, and rapidly lost its biological activity in solution. The inclusion of pepsin in the test systems did not affect the results. Although formulation differences somewhat affected the rate of destruction, acid lability was exhibited by all products examined, except enteric-coated tablets. Amounts of acid considered to be normal in the fasting stomach contents of adults during the time likely for a dose to remain in the stomach caused 70-90% destruction within 15 min after the shells started to rupture. Amounts of hydrochloric acid appreciably less than 1 mEq, representing abnormally small quantities even in the fasting state, caused destruction ranging from 30 to 70% of the doses in 15 min. These results are not reconcilable with published statements that the sensitivity of erythromycin to gastric acid is overcome by providing the antibiotic in the form of stearate salt.
Article
The pharmacokinetics of erythromycin and erythromycin 2'-propanoate were studied in healthy male volunteers following single and repeated doses of erythromycin stearate tablets, erythromycin estolate capsules, and a suspension. Estolate dosages gave rise to higher plasma levels of total drug than the stearate. However, the stearate yielded higher plasma levels of erythromycin base. Absorption of all dosage forms, except the suspension, was delayed, and pharmacokinetic interpretation of both single- and multiple-dose data required incorporation of an absorption lag time. The absorption of erythromycin stearate was inhibited by food and also by low fluid volumes in fasted subjects. Absorption of erythromycin estolate was increased in the presence of food and was not greatly affected by fluid volume. Although single-dose data poorly predicted circulating levels of erythromycin following repeated doses, trends observed after single doses were maintained during chronic treatment.
Article
The influence of various test meals and coadministered water volumes on erythromycin stearate bioavailability from orally dosed film-coated tablets was studied in healthy human subjects. Serum erythromycin levels were uniformly reduced by all test meals, with the reduction in mean peak serum levels varying from 47 to 60%. Serum erythromycin levels also were reduced significantly in fasted individuals when the accompanying water volume was reduced from 250 to 20 ml. The apparent drug absorption rate constant was not influenced by treatments. This result is probably due to rapid degradation of solubilized, unabsorbed drug in the GI tract. Higher and more uniform serum erythromycin levels are obtained when erythromycin stearate tablets are given on an empty stomach together with an adequate water volume.
Article
Erythromycin pharmacokinetics were examined following intravenous infusion to male subjects. The biological half-life of erythromycin in serum was 2 hr in individuals with normal renal function. The half-life varied in cases of reduced renal function, with values of 3.9 and 7.0 hr occurring in two subjects with severe renal impairment. Postinfusion serum erythromycin levels were adequately described by two-compartment model kinetics, and values for the distribution volume of the central compartment and the overall distribution are described. Estimated erythromycin distribution volumes in normal individuals may facilitate calculation of absorption efficiencies of erythromycin and its salts after oral doses.
Article
Six men with borderline hypertension took felodipine 5 mg with water, grapefruit juice, or orange juice. The mean felodipine bioavailability with grapefruit juice was 284 (range 164-469)% of that with water. The dehydrofelodipine/felodipine AUC ratio was lower, diastolic blood pressure lower, and heart rate higher with grapefruit juice than with water. Vasodilatation-related side-effects were more frequent. Orange juice had no such effects. Six healthy men took nifedipine 10 mg with water or grapefruit juice; the bioavailability with grapefruit juice was 134 (108-169)% of that with water.
Article
A high-performance liquid chromatographic method for the determination of plasma concentrations of erythromycin base and 2'-acetylerythromycin, an ester prodrug of erythromycin, is described. tert.-Butyl methyl ether extracts of 1-ml plasma samples (pH 10) were chromatographed on a C18 reversed-phase column. A three-electrode coulometric detector (oxidation potentials +0.65 and +0.85 V) was used for quantitation. Oleandomycin was used as an internal standard. The method has good precision and accuracy, is linear in the range 0.25-7.5 mg/l and has proved to be suitable for pharmacokinetic studies in humans. Correlation with a microbiological assay was satisfactory (r greater than or equal to 0.95), but the chromatographic method gave ca. 30% higher values.
Article
A high-performance liquid chromatographic analysis of erythromycin and its esters in plasma, urine and saliva is presented. A diethyl ether extract of sample was chromatographed on a reversed-phase column and components of the column effluent were monitored by electrochemical detection at +0.9 V (vs. Ag/AgCl). The method sensitivity limit was 10 ng with inter-day coefficients of variation from 3.2 to 10.3%. In order to assess precisely the relative concentrations of erythromycin esters (ethylsuccinate or estolate) and their active by-product erythromycin base, it is necessary to adopt measures preventing their continuous hydrolysis in biological fluids and during sample preparation.
Article
We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.
Article
Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin. A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins. The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver antigens may be recognized as foreign and may trigger, in an exceptional subject, an immunoallergic type of clinical hepatitis.
Article
A simple and sensitive high-performance liquid chromatographic assay was developed for the quantitative determination of major erythromycin components and their potential metabolites or degradation products in plasma and urine. An ether extract of alkalized plasma sample was chromatographed on a reversed-phase column and the components in the column effluent were monitored by an electrochemical detector. The recovery of the drug from extraction was virtually 100%. The detection limits for erythromycin A in plasma were 5-10 ng/ml and 30 ng/ml using 1 and 0.2 ml of sample, respectively. For urine samples, a simple one-step deproteinization with two volumes of acetonitrile was satisfactory for analysis. The method has been evaluated in plasma and urine from dogs receiving oral or intravenous erythromycin A. The standard curves for potential metabolites or degradation products were not constructed due to the lack of sufficient samples.
Article
1 It is well-known that considerable variability and unpredictability in serum concentrations results from orally administered erythromycin. 2 Disposition kinetics and their variability were studies in 24 healthy subjects after a single dose of erythromycin lactobionate and four doses were studied to evaluate dose-related variability in five other subjects. 3 Erythromycin kinetics were adequately described by a classical two compartment open model with little intersubject variability. 4 Dose-related variability occurred. Clearance was independent of dose but T1/2 beta and Vdss increased with dose. 5 Data are presented to show that non-invasive sampling of urine and saliva are of limited value in studying erythromycin pharmacokinetics.
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
To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Article
To examine the effect of grapefruit juice on the disposition of cyclosporine after administration of oral and intravenous doses to healthy male subjects. Subjects received two oral doses of cyclosporine (7.5 mg/kg) and two intravenous doses (2.5 mg/kg infused for 3 hours), with each dose separated by a 1-week washout period. Grapefruit juice (250 ml) was ingested immediately before one oral and one intravenous dose and again 2 hours later. Blood samples were collected for a 24-hour period, and whole blood concentrations of cyclosporine were measured with use of a specific monoclonal radioimmunoassay. Grapefruit juice had no effect on any pharmacokinetic parameter when given with intravenous cyclosporine. After oral administration, grapefruit juice significantly increased peak concentration (936 versus 1340 ng/ml), as well as area under the curve (6722 versus 10,730 ng . hr/ml) but had no effect on elimination half-life. Absolute bioavailability of cyclosporine was increased from 0.22 to 0.36 (average increase, 62%) by grapefruit juice. The lack of effect on systemic clearance after intravenous cyclosporine suggests that grapefruit juice improves oral bioavailability by increasing absorption or reducing gut wall metabolism. The latter is more likely in view of studies that suggest significant gut wall metabolism of cyclosporine by CYP3A enzymes known to be inhibited by components of grapefruit juice.
Article
CYP3A4, a major Phase I xenobiotic metabolizing enzyme present in liver, is also present in human small bowel epithelium where it appears to catalyse significant 'first pass' metabolism of some drugs. To determine whether CYP3A4 or the related enzymes CYP3A3, CYP3A5, and CYP3A7 are present in other regions of the digestive tract, we used CYP3A-specific antibodies to examine histological sections and epithelial microsomes obtained from a human organ donor. CYP3A-related proteins were detected in epithelia throughout the digestive tract and in gastric parietal cells, in pericentral hepatocytes, and in ductular cells of the pancreas. Immunoblot analysis suggested that the major CYP3A protein present in liver, jejunum, colon, and pancreas was CYP3A4 or CYP3A3, whereas CYP3A5 was the major protein present in stomach. Both CYP3A4 and CYP3A5 mRNA were detectable in all regions of the digestive tract using the polymerase chain reaction (PCR); however, only CYP3A4 could be detected by Northern blot analysis. CYP3A7 mRNA was consistently detected only in the liver by PCR and CYP3A3 mRNA was not detected in any of the tissues. We conclude that CYP3A4 and CYP3A5 are present throughout the human digestive tract and that differences in the expression of these enzymes may account for inter-organ differences in the metabolism of CYP3A substrates.
Article
Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 (about 4%), 2D6 (about 2%) and 2B6 (< 1%) were the minor P-450 forms. Differences in some of the P-450 1A2-, 2A6-, 2D6-, 2E1- and 3A4-dependent activities were observed in Japanese and Caucasian populations. No clear sex-related differences in individual P-450 contents and drug- and carcinogen-metabolizing activities were detected in 60 human samples, except that P-450 1A2-dependent activities were found to be higher in mean than in women in the Caucasian population only. A single neonate sample tended to be lower in P-450 1A2-, 2A6- and 2E1-dependent activities. In contrast to rat counterparts, we could not detect apparent developmental changes in P-450 content and activity in humans between 12 and 73 years old. Thus, the results presented in this study provide useful information for the study of drug biotransformation in humans and for the basis of drug toxicities, carcinogenesis and teratogenesis.
Article
An enantioselective method of high specificity and sensitivity for the determination of the enantiomers of two racemic 1,4-dihydropyridine compounds after simultaneous oral (po) and intravenous (iv) administration is reported. The method is suitable for the simultaneous administration by two different routes of a racemic drug labeled with stable isotopes and unlabeled racemate. For workup, an internal racemic standard labeled with a different number of stable isotopes is added. After separation of the enantiomers by chiral stationary-phase high-performance liquid chromatography and subsequent analysis by gas chromatography/mass spectroscopy (GC/MS) with selected ion detection, the R and S enantiomer concentrations arising from i.v. and p.o. administration can be precisely measured because of their mass difference. This method has been applied to assess the disposition of the R and S enantiomers of nimodipine and nitrendipine after simultaneous i.v. and p.o. administration. The assay is highly specific and sensitive, with a limit of quantification per enantiomer of 0.1 ng/mL after extraction of 0.5 mL of human serum samples and monitoring the M- ions in the electron capture, negative ion chemical ionization mode. The calibration curve was linear in the range 0.1-100 ng/mL. Within- and between-day precision were satisfactory (coefficient of variation, < 10%). Enantiomeric excess in the range 0-100% could be accurately determined. Comparison of the enantioselective method with the achiral method (GC/MS only) gave good agreement.
Article
Nifedipine was administered to 12 healthy Nigerian volunteers as a single oral dose of 20 mg capsule under fasting conditions. The pharmacokinetic results were compared with published data using the same protocol and analytical method for 27 Caucasians and 30 South Asians. The area under the plasma concentration-time curve (AUC) of nifedipine in Nigerians (808 +/- 250 ng ml-1 h) was significantly higher (P < 0.001) than that in Caucasians (323 +/- 116 ng ml-1 h) and the difference remained significant (P < 0.001) when corrected for body weight. The elimination half-life was also significantly higher (P < 0.01) in Nigerians (5.03 +/- 1.96 h) than in Caucasians (2.78 +/- 1.11 h). No significant differences were observed between Nigerians and South Asians in either AUC or half-life of nifedipine. The AUC of the nitropyridine metabolite was higher (P < 0.01) in Nigerians (220 +/- 51 ng ml-1 h) compared with that in Caucasians (154 +/- 56 ng ml-1 h) but the difference was not maintained when corrected for body weight. The AUC corrected for body weight and the elimination half-life of the metabolite were significantly higher in South Asians compared with those of Nigerians and Caucasians. The pharmacokinetics of oral nifedipine in Nigerians were similar to those in South Asians and therefore may also arise from a lower systemic clearance compared with Caucasians as has been reported previously for South Asians.
Article
1. The effects of treatment of rat with roxithromycin, erythromycin and troleandomycin as well as other chemicals including typical cytochrome P450 inducers were examined in rat and human liver microsomes. 2. Erythromycin and troleandomycin but not roxithromycin caused slight increases in CYP3A1 levels and the N-demethylation of roxithromycin, erythromycin and troleandomycin and oxidation of nifedipine in rat, but none of these chemicals induced significantly CYP2B1 levels or benzphetamine N-demethylation activities. 3. Dexamethasone and pregnenolone 16 alpha-carbonitrile induced CYP3A1 levels and N-demethylation of roxithromycin, erythromycin and troleandomycin but not of benzphetamine, in rat liver microsomes. Treatment of rat with phenobarbital caused increases in both CYP2B1 and 3A1 levels and all of the N-demethylation activities examined. Phenytoin and metyrapone produced increases in contents of 2B1 and activities of benzphetamine N-demethylation as well as of roxithromycin, erythromycin and troleandomycin, although these two inducers did not induce 3A1 protein significantly. 4. In man, a liver sample that was high in CYP3A4 and nifedipine oxidation activity was found to be the most active in N-demethylation activities towards these substrates examined. In addition, recombinant 3A4 catalysed very efficiently the N-demethylation of roxithromycin, erythromycin and troleandomycin in reconstituted monooxygenase systems. 5. These data suggest that erythromycin and troleandomycin, but not roxithromycin, were able to induce CYP3A1 in rat liver microsomes, and that N-demethylation of roxithromycin, erythromycin and troleandomycin were catalysed mainly by 3A1 (and partly by 2B1) in rat and by 3A4 in man.
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
The intracellular concentration of many steroids and xenobiotics is influenced by the membrane protein P-glycoprotein (Pgp). It has been inferred that the intracellular retention of many drugs that upregulate Pgp or modulate Pgp function might also be affected by Pgp. However, the ability of Pgp to influence the translocation of these drugs needs to be established to understand Pgp's influence upon their pharmacological effect. We utilized two approaches to determine the interaction of several agents with Pgp: (a) an in vitro system, LLC-PK1 cell lines and derivative LLC cell lines stably expressing on the apical membrane either mouse mdr1a or human MDR1 Pgp grown as polarized epithelium in transwell culture to measure translocation of radiolabeled drugs; and (b) an in vivo system, mdr1a nullizygous and wild-type animals, to compare the contribution of Pgp to in vivo distribution of radiolabeled drugs. In combination these complementary approaches identified erythromycin as a drug whose intracellular retention is influenced by Pgp, while the intracellular accumulation and tissue distribution of retinoic acid and benzo(a)pyrene were unaffected by Pgp.
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.
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