Cytochrome P450 Turnover: Regulation of Synthesis and Degradation, Methods for Determining Rates, and Implications for the Prediction of Drug Interactions

In vivo enzyme levels are governed by the rates of de novo enzyme synthesis and degradation. A current lack of consensus on values of the in vivo turnover half-lives of human cytochrome P450 (CYP) enzymes places a significant limitation on the accurate prediction of changes in drug concentration-time profiles associated with interactions involving enzyme induction […]

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A Critical Evaluation of the Experimental Design of Studies of Mechanism-based Enzyme Inhibition, with Implications for In Vitro-In Vivo Extrapolation

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 kinetic parameters (k(inact), K(I), r). […]

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Incorporating In Vitro Information on Drug Metabolism into Clinical Trial Simulations to Assess the Effect of CYP2D6 Polymorphisms on Pharmacokinetics and Pharmacodynamics: Dextromethorphan as a Model Application

In vitro-in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well as the in vitro metabolism and pharmacodynamics of dextromethorphan and its active metabolite dextrorphan, was […]

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A Re-evaluation and Validation of Ontogeny Functions for CYPs 1A2 and 3A4 Based on In Vivo Data

Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in pediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. We report ontogeny functions for these enzymes as pediatric to adult relative intrinsic […]

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Differences in Cytochrome P450-mediated Pharmacokinetics Between Chinese and Caucasian Populations Predicted by Mechanistic Physiologically-based Pharmacokinetic Modeling

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval. We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized […]

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Inter-individual Variability in Levels of Human Microsomal Protein and Hepatocellularity per Gram of Liver

This study sought to determine levels of microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of human liver and their interindividual variability. Triplicate liver samples were used to determine values of MPPGL (n = 20) and HPGL (n = 7) after accounting for the fractional loss of microsomal protein or hepatocytes during processing. Repeated measurements […]

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Accounting for Transporters in Renal Clearance: Towards a Mechanistic Kidney Model (Mech KiM)

The impact of transporters in modulating the disposition of drugs in the liver and their passage across the gut wall has received much more attention than their role in renal excretion, despite the fact that 25–30 % of drugs are cleared predominantly by renal clearance and renal transporters contribute significantly to this process. Thus there […]

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Prediction of Time-dependent CYP3A4 Drug-drug Interactions by Physiologically-based Pharmacokinetic Modeling: Impact of Inactivation Parameters and Enzyme Turnover

Predicting the magnitude of time-dependent metabolic drug-drug (mDDIs) interactions involving cytochrome P-450 3A4 (CYP3A4) from in vitro data requires accurate knowledge of the inactivation parameters of the inhibitor (KI), kinact) and of the turnover of the enzyme (kdeg) in both the gut and the liver. We have predicted the magnitude of mDDIs observed in 29 […]

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