European Journal of Drug Metabolism and Pharmacokinetics (EUR J DRUG METAB PH )

Description

The European Journal of Drug Metabolism and Pharmacokinetics addresses all aspects of pre-clinical and clinical pharmacokinetics, including drug disposition, drug metabolism, drug transport, drug interactions, bioavailability and biopharmacy. The journal welcomes publications in the field of pharmacokinetic modeling. Analytical methods validation and bioequivalence studies will not be considered for publication. The journal publishes original articles, short preliminary communications, review articles on special topics, and conference proceedings. The European Journal of Drug Metabolism and Pharmacokinetics publishes four issues a year.

  • Impact factor
    1.31
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    Impact factor
  • 5-year impact
    0.84
  • Cited half-life
    0.00
  • Immediacy index
    0.30
  • Eigenfactor
    0.00
  • Article influence
    0.19
  • Website
    European Journal of Drug Metabolism and Pharmacokinetics website
  • Other titles
    European journal of drug metabolism and pharmacokinetics
  • ISSN
    0378-7966
  • OCLC
    2181264
  • Material type
    Periodical
  • Document type
    Journal / Magazine / Newspaper

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Herb-drug interaction strongly limits the clinical utilization of herbs and drugs. Irinotecan-induced diarrhea is closely related with the UDP-glucuronosyltransferase 1A1-catalyzed glucuronidation of SN-38 which has been widely regarded to be the toxic substance basis of irinotecan. The present study aims to determine the influence of herbal component psoralidin toward the toxicity of irinotecan. In vitro inhibition potential of psoralidin toward the glucuronidation of SN-38 was firstly investigated using human intestinal microsomes incubation system. Dose-dependent inhibition of psoralidin toward SN-38 glucuronidation was observed. Furthermore, Dixon plot showed that the intersection point was located in the second quadrant, indicating the competitive inhibition of psoralidin toward the glucuronidation of SN-38. Through the data fitting using competitive inhibition fitting equation, the inhibition kinetic parameter (K i) was calculated to be 5.8 μM. The translation of these in vitro data into the in vivo situation showed that pre-treatment with psoralidin significantly increased the toxicity of irinotecan, as indicated by the increased body weight loss and more severe colon histology damage. All these data indicated the herb-drug interaction between irinotecan and psoralidin-containing herbs.
    European Journal of Drug Metabolism and Pharmacokinetics 09/2014;
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    ABSTRACT: The tolerability and pharmacokinetics of disodium folinate may vary with different races, and these variations might result in different outcomes. This study assessed the tolerability and pharmacokinetics of disodium folinate following single intravenous doses in healthy Chinese subjects, with gender factor also taken into account. Subjects were randomized to receive a single dose of disodium folinate at 20, 200, or 300 mg/m(2) administered intravenously over a time period of 10 min. Sequential blood samples were collected at regular intervals over 24 h after dosing and were analyzed using a validated high-performance liquid chromatography (HPLC) method. Pharmacokinetic parameters, including C max, AUC0-t, t 1/2, V d, and CL, were calculated using non-compartmental models. Tolerability was assessed by collecting adverse events (AEs) and monitoring vital signs, physical examinations, laboratory tests, and electrocardiograms. Following a single intravenous administration of disodium folinate 20, 200, and 300 mg/m(2), the mean (standard deviation) pharmacokinetic parameters were as follows: C max = 5.18 (0.58), 47.80 (10.10), and 69.93 (9.72) µg/mL; AUC0-t = 25.85 (3.36), 194.53 (30.18), and 355.26 (35.31) µg h/mL; AUC0-∞ = 30.24 (6.19), 215.43 (27.34), and 417.88 (54.81) µg h/mL; t 1/2 = 8.77 (2.57), 7.64 (1.81), and 9.08 (1.64) h; CL = 1.12 (0.18), 1.55(0.25), and 0.78 (0.09) L/h; V d = 13.75 (2.61), 17.38 (6.44), and 10.05 (1.49) L, respectively. The mean C max, AUC0-t, and AUC0-∞ increased in a dose-proportional manner. No significant differences in pharmacokinetic parameters were noted by gender. The most common AEs reported were mild redness at the injection site and neurological symptoms (headache, dizziness, and fatigue).
    European Journal of Drug Metabolism and Pharmacokinetics 08/2014;
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    ABSTRACT: Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-norprogesterone, is an orally active drug with a strong affinity for the progesterone receptor. NOMAC inhibits ovulation and is devoid of undesirable androgenic and estrogenic activities. The aim of this study was to evaluate the pharmacokinetics, tissue distribution, and excretion of NOMAC in female rats. Sprague-Dawley female rats were orally administered a single dose of NOMAC (10, 20 or 40 mg/kg) and drug plasma concentrations at different times were determined by RP-HPLC. Tissue distribution at 1, 2, and 4 h and excretion of NOMAC into bile, urine, and feces after dosing were investigated. The results showed that NOMAC was rapidly absorbed after oral administration, with [Formula: see text] of 1-2 h. The plasma concentration-time curves were fitted in a two-compartment model. The exposure to NOMAC ([Formula: see text] and [Formula: see text]) increased dose proportionally from 10 to 40 mg/kg. The average CL and [Formula: see text] were 5.58 L/(h·kg) and 10.8 h, respectively. The highest concentrations of NOMAC in ovary, liver, kidney, lung, heart, brain, spleen, muscle, and uterus were observed at 2 h, whereas the highest concentrations in stomach, pituitary, and hypothalamus appeared at 1 h. The total cumulative excretion of NOMAC in feces (0-72 h), urine (0-72 h), and bile (0-48 h) was ~1.06, 0.03, and 0.08 % of the oral administered dose, respectively. This study indicated that NOMAC had a widespread distribution in tissues, including ovary, pituitary, and hypothalamus, which are main target tissues where NOMAC inhibits ovulation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation was found in the drug elimination; however, it did not significantly affect [Formula: see text].
    European Journal of Drug Metabolism and Pharmacokinetics 08/2014;
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    ABSTRACT: This study aimed to investigate the effects of cytochrome P450 2D6*10 (100C > T, rs1065852) genotype on the pharmacokinetics of dimemorfan in healthy Chinese subjects. Data were evaluated from 24 subjects in two pharmacokinetic studies who received an oral dose of 40 mg of dimemorfan syrup (n = 12) or dimemorfan tablet (n = 12) after providing written informed consent and being divided into three groups: subjects with CYP2D6*10 CC (n = 5), CYP2D6*10 CT (n = 11) and CYP2D6*10 TT (n = 8). CC homozygotes and CT heterozygotes were defined to be C allele carriers. The CYP2D6*10 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Dimemorfan was measured by LC-MS/MS. There was significant difference in C max, AUC0-t , AUC0-inf, V z , and CL values of dimemorfan observed among the three CYP2D6*10 genotype groups (GLM, (a) P < 0.05, co-dominant model). CYP2D6*10 under the recessive model (CC + TC vs TT) was significantly associated with pharmacokinetics of dimemorfan ((c) P < 0.05). The C max values were significantly higher in subjects with CYP2D6*10 TT (8.06 ± 4.43 ng/mL) than CYP2D6*10 CC (3.41 ± 2.79 ng/mL), CYP2D6*10 CT (3.11 ± 2.47 ng/mL), so was AUC0-inf. V z /F and CL/F of subjects with CYP2D6*10 TT homozygotes were the lowest. We demonstrated that cytochrome P450 2D6*10 (100C > T, rs1065852) polymorphism can affect the pharmacokinetics of dimemorfan in humans, not dosage forms.
    European Journal of Drug Metabolism and Pharmacokinetics 08/2014;
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    ABSTRACT: The cytolytic protein perforin is a key component of the immune response and is implicated in a number of human pathologies and therapy-induced conditions. A novel series of small molecule inhibitors of perforin function have been developed as potential immunosuppressive agents. The pharmacokinetics and metabolic stability of a series of 16 inhibitors of perforin was evaluated in male CD1 mice following intravenous administration. The compounds were well tolerated 6 h after dosing. After intravenous administration at 5 mg/kg, maximum plasma concentrations ranged from 532 ± 200 to 10,061 ± 12 ng/mL across the series. Plasma concentrations were greater than the concentrations required for in vitro inhibitory activity for 11 of the compounds. Following an initial rapid distribution phase, the elimination half-life values for the series ranged from 0.82 ± 0.25 to 4.38 ± 4.48 h. All compounds in the series were susceptible to oxidative biotransformation. Following incubations with microsomal preparations, a tenfold range in in vitro half-life was observed across the series. The data suggests that oxidative biotransformation was not singularly responsible for clearance of the compounds and no direct relationship between microsomal clearance and plasma clearance was observed. Structural modifications however, do provide some information as to the relative microsomal stability of the compounds, which may be useful for further drug development.
    European Journal of Drug Metabolism and Pharmacokinetics 08/2014;
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    ABSTRACT: To report a sinus bradycardia induced by metoprolol and terbinafine drug–drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient’s sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol’s clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2014;
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    ABSTRACT: Quercetin and Rutin are most common flavone constituents of some herb extracts such as Hippophae rhamnoides L. Inter and intra herb pharmacokinetics interactions of Quercetin and Rutin were investigated in the present study. Pharmacokinetic study was investigated in the two groups of rats (n = 6) for pharmacokinetic interactions between the Quercetin and Rutin (2.5 mg/kg) mixture treated alone with European patented polyherbal formulation containing equivalent weight of the above. The total plasma concentrations of Quercetin and Rutin were determined by liquid chromatography mass spectrometry (LC–MS). A method was developed and validated according to the ICH guidelines. The results of the present study shows that there are great differences in the pharmacokinetics of Quercetin and Rutin when they are administered together and from the polyherbal formulation which will be interacted by many other constituents. The bioavailability of Quercetin was lowered from the polyherbal formulation when compared with the co-administration, whereas the Rutin bioavailability has increased from the polyherbal formulation when compared with the co-administration. The maximum plasma concentration of Quercetin from coadministration and polyherbal formulation was 165.3 ± 31.9 and 90.8 ± 21.4 ng/mL, respectively, whereas in the case of Rutin it was 61.1 ± 29.3 and 121.7 ± 19.2 ng/mL. After polyherbal formulation administration to rats the AUC0–24, AUC0–? and AUMC0–? of both Quercetin and Rutin significantly increased when compared to co-administration. The above results proved that inter and intra herb pharmacokinetic interactions between Quercetin and Rutin. Possible interactions of the other constituents with hydrolyzing enzymes in the formulation enhances the oral bioavailability of Rutin. Accordingly besides the drug herb interactions, inter and intra herb interaction might be brought into view with the wide use of herbal remedies.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2014;
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    ABSTRACT: Micafungin is an echinocandin with potent activity against a broad range of fungal species, including Candida species. The pharmacokinetic and safety profiles of micafungin have been evaluated in individuals with mild-to-moderate hepatic dysfunction, but not in individuals with severe hepatic dysfunction. Therefore, the present study assessed the pharmacokinetics and safety of a single 100 mg dose of micafungin in healthy subjects (n = 8) and subjects with severe hepatic dysfunction (n = 8). Mean maximum plasma concentration of micafungin and mean area under the plasma micafungin concentration–time curve extrapolated to infinity were lower in subjects with severe hepatic dysfunction (7.3 ± 2.4 µg/mL and 100.1 ± 34.5 h·μg/mL, respectively) than in subjects with normal hepatic function (10.3 ± 2.5 µg/mL and 142.4 ± 28.9 h·μg/mL, respectively). Mean clearance was higher in subjects with severe hepatic dysfunction (1,098 ± 347 mL/h) than in subjects with normal hepatic function (728 ± 149 mL/h). Concentrations of albumin in subjects with severe hepatic dysfunction were lower. Assessments of micafungin plasma protein binding suggested that the higher clearance in subjects with severe hepatic dysfunction may be due to higher unbound concentrations. However, the magnitude of the differences was not considered clinically meaningful and is comparable with exposures reported elsewhere for a 100-mg dose in patients treated for invasive candidiasis. Thus, dose adjustment in subjects with severe hepatic dysfunction is not warranted. Micafungin was well tolerated in all subjects throughout the study.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2014;
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    ABSTRACT: Tectorigenin (Te) is a main active component in the flowers of Pueraria thomsonii Benth. and the rhizomes of Belamcanda chinensis (L.) DC. Previously, we have reported the pharmacokinetic properties of Te in rat plasma. The purpose of this study was to investigate the urinary excretion of Te after oral administration to rats at different dose levels. Using UHPLC/Q-TOFMS, totally 26 metabolites were detected in rat urine after oral administration of Te at dose of 65 and 130 mg/kg. Among them, nine metabolites, Te, tectorigenin-7-O-glucuronide-4'-sulfate (Te-7G-4'S), tectorigenin-7-O-glucuronide (Te-7G), tectorigenin-7-O-sulfate (Te-7S), tectorigenin-4'-O-glucuronide (Te-4'S), isotectorigenin, genistein, irisolidone-7-O-glucuronide (Ir-7G), and irisolidone, were identified by comparing the retention time, UV and MS spectra with those of authentic standards. A UHPLC/Q-TOFMS method for simultaneous quantification and semi-quantification of all the metabolites in urine was developed. The cumulative urinary excretions of Te and the major metabolite Te-7G were 1.99 and 5.80 μmol at 65 mg/kg, 3.05 and 6.48 μmol at 130 mg/kg, accounted for 4.17 % and 15.8, 2.81 and 9.49 % of administrated Te, respectively. The excretion rates of Te-7G, Te-7G-4'S, Ir-7G, and Te reached a maximum between 12 and 24 h after oral dosing at 65 and 130 mg/kg. The cumulative urine excretion rates of Te were 23.1 and 20.1 % within 72 h at 65 and 130 mg/kg, respectively. These results suggested that the glucuronidation was the primary metabolic pathway especially at low dose level.
    European Journal of Drug Metabolism and Pharmacokinetics 05/2014;
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    ABSTRACT: GNF-351 is a candidate drug used to treat some diseases through antagonizing aryl hydrocarbon receptor. In the present study, molecular docking method was employed to understand the interaction between ketoconazole and GNF-351. The structure of cytochrome P450 (CYP) 3A4 was obtained from protein data bank, and 2-dimensional structure of GNF-351 with standard bond lengths and angles was drawn using chemdraw software. 30 possible binding orientations was generated and docked into the X-ray crystallographic structure of human CYP3A4. The predicted binding mode of GNF-351 into CYP3A4 appeared to adopt an orientation with interactions between their flat aromatic rings and Phe 302 and Phe 304. The comparison for the binding of GNF-351 and ketoconazole into the activity cavity indicated that they exhibited similar distance towards heme, indicating the potential interaction between GNF-351 and ketoconazole. These data remind us the necessary monitoring when future utilization between GNF-351 and ketoconazole.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: The compound series of traditional anticholinergics [atropine (Atr), anisodamine (Ani), anisodine (AT3), and scopolamine (Sco)], naturally occurring belladonna alkaloid, have been approved for numerous therapeutic uses since 1970s. Tiotropium, a novel M receptor antagonist for the treatment of chronic obstructive pulmonary disease, was structurally modified based on atropine-like drugs. Clinical phenomena suggested that the changes of substituent group were related to the pharmacokinetic and pharmacodynamic characteristics of the agents. In an attempt to compare the pharmacokinetics of the series of anticholinergics and investigate the subsets motivating selective anticholinergic potencies, a sensitive LC-MS/MS method was established to analyze the differences of pharmacokinetic parameters. In this paper, we determined the pharmacokinetics of atropine, anisodamine, anisodine, scopolamine, and tiotropium after i.v. and i.g. single dose administration. After i.v. administration, the maximum drug plasma concentrations (C max) of Atr, Ani, AT3, and Sco were 274.25 ± 53.66, 267.50 ± 33.16, 340.50 ± 44.52, and 483.75 ± 78.13 ng/mL. Tiotropium had a slightly higher area under the curve with a significant increase of C max value. Because of their partial solubility, Atr, Ani, AT3, and Sco had different bioavailability in rats of 21.62, 10.78, 80.45 and 2.52 %, respectively. Following i.g. administration of tiotropium, the C max value below 20 ng/mL revealed the very low oral absorption. The urinary excretion rates of Atr, Ani, AT3, Sco and tiotropium were 11.33, 54.86, 32.67, 8.69 and 73.91 %. This work provided relatively comprehensive preclinical data on the series of anticholinergics, which may be used to explain the clinical adverse effects and applications.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: The 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors known as "statins" are widely prescribed for the management of dyslipidemia. In spite of their muscle toxicity, use of statins has alarmingly increased worldwide. A recent report suggests that vitamin D (VD) levels are closely associated with lipid lowering activity and muscular toxicity of statins. However, data are limited and inconclusive. The present study was undertaken to investigate the effect of VD supplementation on the bioavailability and lipid lowering effect of simvastatin (ST). Adult Sprague-Dawley male rats (250 ± 10 g) were divided into four groups including control, ST (100 mg/kg/day), VD (100 μg/kg/day) and ST + VD group, respectively. After the dosing period of 8 days the animals were sacrificed and the blood was collected for the analysis of ST, its active metabolite simvastatin acid (STA), total cholesterol, triglyceride and liver enzymes including aspartate transaminase and alanine transaminase. The result of this study showed a significant decrease in the level of cholesterol and triglyceride in ST alone treated group, whereas VD alone failed to alter the blood lipid levels. Concomitant treatment with VD produced significant decrease in the bioavailability of ST and STA. However, there was no significant difference in the level of cholesterol in ST alone and in ST + VD treated group. Our results on the liver enzyme suggest that ST alone or in combination with VD does not produce any hepatotoxicity. Further studies using VD along with various statins for a longer duration are suggested.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: The purpose of this work was to develop hollow calcium pectinate beads for floating pulsatile release of metoprolol tartrate intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, hollow/porous beads were prepared by simple process of acid-base reaction during ionotropic cross-linking using low methoxy pectin, xanthan gum, sodium carboxy methyl cellulose, guar gum, locust bean, gellan gum and calcium chloride as a cross-linking agent. Based on the preliminary studies optimized polymers were selected for formulation design with different polymers ratio concentrations. The obtained floating beads were studied for entrapment efficiency, buoyancy study, swelling index, surface morphology, in vitro release, stability studies and in vivo floating study. The floating beads obtained were porous, float up to 12-24 h. The radiological studies (X-rays) pointed out the capability of the system to release drug in lower parts of GIT after a programmed lag time for hypertension. The floating beads provided expected two-phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. From the accelerated stability studies, it was observed that the formulations are quite stable. All formulations followed first-order release kinetics by diffusion mechanism. This approach suggested the use of hollow calcium pectinate microparticles as promising floating pulsatile drug delivery system for site- and time-specific release of drugs acting as per chronotherapy of diseases.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: Chinese herbal medicines such as hawthorn, salvia, etc., are frequently combined with statins so as to treat cardiovascular diseases more effectively. Chinese herbal medicines contain many kinds of active components, which may have drug-drug interactions with statins. This study aims to explore the effect and mechanism by which ursolic acid affects OATP1B1-mediated transport of rosuvastatin. This study will explore the effect of ursolic acid on OAPT1B1-mediated transport of rosuvastatin in the different cell systems. Given the genetic polymorphisms of OATP1B1, simultaneously, this study will further explore the effect of ursolic acid on OATP1B1 (521T>C)-mediated transport of rosuvastatin. When the concentration of ursolic acid was 1.8 and 18 µM, it showed that ursolic acid significantly inhibits the uptake of rosuvastatin in both OATP1B1*1a-HEK 293T cells and OATP1B1*5-HEK 293T cells. The reduction of OATP1B1*1a transport of rosuvastatin were 34.60 ± 2.99 and 66.08 ± 1.83 %, and for OATP1B1*5 were 34.27 ± 7.08 % and 66.95 ± 1.14 %. Inhibitory parameters of IC50 were 6.25 ± 0.42 and 6.07 ± 0.57 µM, respectively. This study suggests that ursolic acid can affect the uptake of rosuvastatin in hepatocytes by inhibiting the transport of OATP1B1, and gene mutation of OATP1B1 may cause different effects on its transport of rosuvastatin.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: The present study was conducted to investigate the effects of some commonly used herbs namely Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetics of sildenafil in beagle dogs. The study design involved four treatments in a non-balanced crossover design. Sildenafil was given one tablet 100 mg orally to each dog and blood samples were obtained. After a suitable washout period, animals were commenced on a specific herb treatment for 1 week. Blood samples were withdrawn at different time intervals and sildenafil was analyzed by HPLC method. Oral administration of Nigella sativa resulted in reduction of AUC0-∞, C max and t 1/2 as compared to the control. Treatment of Lepidium sativum resulted in a significant reduction in the C max and AUC. There were no significant differences between the rests of the pharmacokinetic parameters relative to those of the control. For Trigonella foenum-graecum, the effects were similar to those obtained in case of Lepidium sativum. It was concluded that concurrent use of investigated herbs alters the pharmacokinetics of sildenafil. Co-administration of investigated herbs should be cautious since their concomitant use might result in decrease in sildenafil bioavailability.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: Chagas disease is an endemic infection in Latin America with a high health impact. Caused by the parasite Trypanosoma cruzi, it has expanded to non-endemic regions such as North America and European countries via immigration of infected people. This infectious disease has been rising in the ranking of international health priorities due to the growing migration flows from endemic to non-endemic areas. Benznidazole (BZN), a nitroheterocyclic drug, is one of the two trypanocidal drugs currently in clinical use, associated with significant adverse drug reactions (ADRs). Mammalian metabolism of BNZ has been poorly studied, including the potential role of metabolites on both toxicity and anti-parasitic activity. High-resolution UPLC/MS/MS was used to analyze three plasma samples obtained from pediatric patients under BNZ treatment in steady state. Spectroscopic and structural criteria were applied to identify BNZ and accompanying substances from chromatographic signals. From all detected species, two can be undoubtedly associated with the BNZ and N-benzylacetamide molecules, the second one being a fragment of the parent drug (BZN). From the obtained results, two hypotheses could be formulated. The first one is to relate the presence of N-benzyl acetamide with the hepatic metabolism of BNZ. The second hypothesis has to do with the possible trypanocidal activity of this metabolite, as well as its role in the development of side effects, associated with the pharmacotherapy. Complementary studies should be carried out to determine the possible association of this metabolite with the BNZ treatment stages, patient's clinical features, ADRs, and trypanocidal effectiveness.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: The use of mefloquine (MQ) for antimalarial treatment and prophylaxis has diminished largely in response to concerns about its neurologic side effects. An analog campaign designed to maintain the efficacy of MQ while minimizing blood-brain barrier (BBB) penetration has resulted in the synthesis of a prodrug with comparable-to-superior in vivo efficacy versus mefloquine in a P. berghei mouse model while exhibiting a sixfold reduction in CNS drug levels. The prodrug, WR319670, performed poorly compared to MQ in in vitro efficacy assays, but had promising in vitro permeability in an MDCK-MDR1 cell line BBB permeability screen. Its metabolite, WR308245, exhibited high predicted BBB penetration with excellent in vitro efficacy. Both WR319670 and WR308245 cured 5/5 animals in separate in vivo efficacy studies. The in vivo efficacy of WR319670 was thought to be due to the formation of a more active metabolite, specifically WR308245. This was supported by pharmacokinetics studies in non-infected mice, which showed that both IV and oral administration of WR319670 produced essentially identical levels of WR319670 and WR308245 in both plasma and brain samples at all time points. In these studies, the levels of WR308245 in the brain were 1/4 and 1/6 that of MQ in similar IV and oral studies, respectively. These data show that the use of WR319670 as an antimalarial prodrug was able to maintain efficacy in in vivo efficacy screens, while significantly lowering overall penetration of drug and metabolites across the BBB.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: Indacaterol is an inhaled, ultra-long-acting β2-agonist that provides 24-h bronchodilation with once-daily dosing in patients with chronic obstructive pulmonary disorder. This study evaluated the pharmacokinetics, safety, and tolerability of multiple daily inhaled doses of indacaterol 150 or 300 μg once daily in healthy Chinese volunteers. This was a single-center, randomized, double-blind, multiple-dose, parallel-group study, placebo-controlled trial including two doses of indacaterol: 150 and 300 μg. Serum indacaterol was quantified using high-performance liquid chromatography-mass spectrometry with a lower limit of quantification of 0.01 ng/mL. The pharmacokinetic parameters were analyzed using non-compartmental analysis and included C max, T max, and AUC0-24h on Day 1 and AUC0-24h,ss, C max,ss, C min,ss, C av,ss, T max,ss, T 1/2, T 1/2,acc, CL/F, V z/F, and R acc on Day 14 (after repeated once-daily doses). Safety analyses were recorded using physical examination, biochemical tests, and ECG. Indacaterol steady state was achieved after 12-14 days of daily dosing. The mean effective half-life of indacaterol (based on drug accumulation at steady state) was 33.9 and 35.8 h for 150 and 300 μg, respectively. Systemic exposure to indacaterol increased 1.27 and 1.34-fold between the 150- and 300-μg doses on Day 1 (first dose) and Day 14 (repeated dose), respectively. Indacaterol 150 and 300 μg were safe and well tolerated in these volunteers. The pharmacokinetics of multiple inhaled doses of indacaterol 150 and 300 μg (for 14 days) were consistent with moderate systemic accumulation at steady state after repeated once-daily inhalation in healthy Chinese volunteers.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: G004 is a novel sulfonylurea hypoglycemic drug which aimed at reducing macro- and micro-vascular complications as well as controlling glucose excursion in type 2 diabetes mellitus. The pharmacokinetics of G004 in rats was sex- and dose-dependent over the dose range of 1-10 mg kg(-1). The mean AUC values in the female rats were fivefold higher than those in males. Drug blood and tissue levels in female rats were higher than the most counterparts of males. Compared with male rats, G004 was eliminated slowly from female rats in the bile, urine and feces. Consistent with the in vivo observations, marked sex-related difference of the metabolizing activity between the male and female liver microsomes (RLM) was observed. The intrinsic clearance (V max/K m) of G004 was 3.1-fold larger in the RLM from male than female rats. Seventeen oxidative metabolites were identified in rat liver microsomes. The amount of three metabolites of G004 showed relatively sex-related difference in RLM incubations. CYP2C11 was demonstrated mainly contributing to the sex-related differences in the pharmacokinetics and disposition of G004 in rats.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;
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    ABSTRACT: (R)-2-Amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one (GNE-892) is an orally administered inhibitor of β-secretase 1 (β-site amyloid precursor protein cleaving enzyme 1, BACE1) that was developed as an intervention therapy against Alzheimer's disease. A clinical microdosing strategy was being considered for de-risking the potential pharmacokinetic liabilities of GNE-892. We tested whether dose-proportionality was observed in cynomolgus monkey as proof-of-concept for a human microdosing study. With cryopreserved monkey hepatocytes, concentration-dependency for substrate turnover and the relative contribution of P450- versus AO-mediated metabolism were observed. Characterization of the kinetics of these metabolic pathways demonstrated differences in the affinities of P450 and AO for GNE-892, which supported the metabolic profiles that had been obtained. To test if this metabolic shift occurred in vivo, mass balance studies in monkeys were conducted at doses of 0.085 and 15 mg/kg. Plasma exposure of GNE-892 following oral administration was more than 20-fold greater than dose proportional at the high-dose. P-gp-mediated efflux was unable to explain the discrepancy. The profiles of metabolites in circulation and excreta were indicative that oxidative metabolism limited the exposure to unchanged GNE-892 at the low dose. Further, the in vivo data supported the concentration-dependent metabolic shift between P450 and AO. In conclusion, microdosing of GNE-892 was not predictive of pharmacokinetics at a more pharmacologically relevant dose due to saturable absorption and metabolism. Therefore, it is important to consider ADME liabilities and their potential concentration-dependency when deciding upon a clinical microdosing strategy.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014;

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