Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in rats in vitro and in vivo.
ABSTRACT It has been reported that hepatic cytochrome P450 (CYP)2C9 and CYP3A4 are responsible for the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in humans. However, in-vivo studies in rats have not been reported.
Sildenafil (20 mg/kg) was administered intravenously to rats pretreated with sulfaphenazole, cimetidine, quinine hydrochloride or troleandomycin, inhibitors of CYP2C6, CYP2C11, CYP2D subfamily and CYP3A1/2, respectively. In-vitro studies using rat liver microsomes were also performed.
The area under the plasma-concentration time curve (AUC) was increased and clearance of sildenafil decreased in rats pretreated with cimetidine or troleandomycin. The AUC ratio for N-desmethylsildenafil (0-4 h) : sildenafil (0-infinity) was significantly decreased only in rats pretreated with cimetidine. Similar results were obtained in the in-vitro study using rat liver microsomes.
Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N-desmethylsildenafil in humans.
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ABSTRACT: The LC (liver cirrhosis induced by N-dimethylnitrosamine) and LCD (LC with diabetes mellitus induced by streptozotocin) rats have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. The changes in the pharmacokinetics of drugs (mainly non-renal clearance, CLNR ) in LC and LCD rats reported in the literatures compared with respective control rats were reviewed. In this review, we mainly explain the changes in the CLNR s of drugs (which are mainly metabolized via hepatic microsomal cytochrome P 450 s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CLint ; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (fp ) and hepatic blood flow rate (QH ) depending on the hepatic excretion ratio of the drug. Generally, the changes in CLNR s of drugs in LC and LCD rats could be well explained by the above-mentioned three factors. The mechanism of urinary excretions of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans. This article is protected by copyright. All rights reserved.Biopharmaceutics & Drug Disposition 05/2014; · 2.09 Impact Factor
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ABSTRACT: In this study, we evaluated inhibitory potentials of popularly-consumed berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) as herbal supplements on UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in vitro. We also investigated the potential herb-drug interaction via UGT1A1 inhibition by blueberry in vivo. We demonstrated that these berries had only weak inhibitory effects on the five UGTs. Bilberry and elderberry had no apparent inhibitions. Blueberry weakly inhibited UGT1A1 with an IC50 value of 62.4 ± 4.40 μg/mL and a Ki value of 53.1 μg/mL. Blueberry also weakly inhibited UGT2B7 with an IC50 value of 147 ± 11.1 μg/mL. In addition, cranberry weakly inhibited UGT1A9 activity (IC50 = 458 ± 49.7 μg/mL) and raspberry ketones weakly inhibited UGT2B7 activity (IC50 = 248 ± 28.2 μg/mL). Among tested berries, blueberry showed the lowest IC50 value in the inhibition of UGT1A1 in vitro. However, the co-administration of blueberry had no effect on the pharmacokinetics of irinotecan and its active metabolite, SN-38, which was mainly eliminated via UGT1A1, in vivo. Our data suggests that these five berries are unlikely to cause clinically significant herb-drug interactions mediated via inhibition of UGT enzymes involved in drug metabolism. These findings should enable an understanding of herb-drug interactions for the safe use of popularly-consumed berries.Food and Chemical Toxicology 07/2014; 72. · 3.01 Impact Factor
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ABSTRACT: A rapid, sensitive, simple and accurate LC-MS/MS method for the simultaneous quantitation of caffeine, and its three primary metabolites, theobromine, paraxanthine, and theophylline, in rat plasma was developed and validated. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column using 1μg/mL acetaminophen as an internal standard. Each sample was run at 0.5mL/min for a total run time of 7min/sample. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with positive electrospray ionization. The lower limit of quantification was 5ng/mL for all analytes with linear ranges up to 5000ng/mL for caffeine and 1000ng/mL for its metabolites. The coefficient of variation for assay precision was less than 12.6%, with an accuracy of 93.5-114%. The assay was successfully applied to determine plasma concentrations of caffeine, theobromine, paraxanthine, and theophylline in rat administered various energy drinks containing the same caffeine content. Various energy drinks exhibited considerable variability in the pharmacokinetic profiles of caffeine and its three primary metabolites, even containing the same caffeine. Different additives of energy drinks might contribute to these results.Food Chemistry 12/2013; 141(3):2735-42. · 3.33 Impact Factor