Learn More
AIMS Many substrates of cytochrome P450 (CYP) 3A4 are used for in vitro investigations of drug metabolism and potential drug-drug interactions. The aim of the present study was to determine the relationship between 10 commonly used CYP3A4 probes using modifiers with a range of inhibitory potency. METHODS The effects of 34 compounds on CYP3A4-mediated(More)
Expression levels of the major human sulfotransferases (SULTs) involved in xenobiotic detoxification in a range of human tissues (i.e., SULT "pies") are not available in a form allowing comparison between tissues and individuals. Here we have determined, by quantitative immunoblotting, expression levels for the five principal human SULTs-SULT1A1, SULT1A3/4,(More)
Cultured cryopreserved human hepatocytes are extensively used as a model system for studying drug metabolism, although they remain poorly characterized in respect of the major conjugation reactions glucuronidation and sulfation. Using paracetamol (acetaminophen), we assessed eleven samples of cryopreserved human hepatocytes for their suitability to(More)
1. The potential of ketoconazole and sulphaphenazole to inhibit specific P450 enzyme activities (1A2, 2A6, 2B6, 2C9/8, 2C19, 2D6, 2E1, 3A and 4A) was investigated using human liver microsomes. 2. Ketoconazole demonstrated an inhibitory effect on cyclosporine oxidase and testosterone 6 beta-hydroxylase activities, with mean IC50's of 0.19 and 0.22 microM(More)
The published literature on mechanism based inhibition (MBI) of CYPs was evaluated with respect to experimental design, methodology and data analysis. Significant variation was apparent in the dilution factor, ratio of preincubation to incubation times and probe substrate concentrations used, and there were some anomalies in the estimation of associated(More)
Physiologically based pharmacokinetic modeling and simulation can be used to predict the pharmacokinetics of drugs in human populations and to explore the effects of varying physiologic parameters that result from aging, ethnicity, or disease. In addition, the effects of concomitant medications on drug exposure can be investigated; prediction of the(More)
Several reports in the literature present the utility and value of in vitro drug-metabolizing enzyme inhibition data to predict in vivo drug-drug interactions in humans. A retrospective analysis has been conducted for 26 GlaxoSmithKline (GSK) drugs and drug candidates for which in vitro inhibition parameters have been determined, and clinical drug(More)
1. The metabolism of granisetron was investigated in human liver microsomes to identify the specific forms of cytochrome P450 responsible. 2. 7-hydroxy and 9'-desmethyl granisetron were identified as the major products of metabolism following incubation of granisetron with human liver microsomes. At low, clinically relevant, concentrations of granisetron(More)
Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation(More)
1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were(More)