In vitro–in vivo extrapolation of metabolic clearance using human liver microsomes: factors showing variability and their normalization
- 12 March 2020
- journal article
- research article
- Published by Taylor & Francis Ltd in Xenobiotica
- Vol. 50 (9), 1064-1075
- https://doi.org/10.1080/00498254.2020.1738592
Abstract
In vitro-in vivo extrapolation (IVIVE) using human liver microsomes has been widely used to predict metabolic clearance, but some of the factors used in the process of prediction show variability for the same compound: notably, microsomal intrinsic clearance values corrected by the unbound fraction (CLint, u), physiological parameters used for scale-up, and the source of in vivo clearance data. The purpose of this study was to assess the correlation between in vitro and in vivo CLint with a focus on factors showing variability using four cytochrome P450 (CYP) 3A substrates. We surveyed in vivo clearance values in literature and also determined the microsomal CLint, u values. A scaling factor (SFdirect) was defined as in vivo CLint divided by the microsomal CLint, u, which ranged from 1190 to 2310 (mg protein per kg body weight). The application of a mean SFdirect of 1600 (mg protein per kg body weight) and further normalization by the microsomal CLint, u values of midazolam, the most commonly used substrate, resulted in improved prediction accuracy for CLint, u values from various microsomal batches. The results suggest the normalization of variability might be useful for predicting the in vivo CLint.Keywords
This publication has 82 references indexed in Scilit:
- Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolamBritish Journal of Clinical Pharmacology, 2010
- Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug DevelopmentThe AAPS Journal, 2009
- Standard liver volume in the caucasian populationLiver Transplantation and Surgery, 1999
- Cytochrome P450 3AClinical Pharmacokinetics, 1999
- Pharmacokinetic-Pharmacodynamic Modelling of the Interaction between Flumazenil and Midazolam in Volunteers by Aperiodic EEG AnalysisClinical Pharmacokinetics, 1991
- Pharmacokinetics and absolute bioavailability of diltiazem in humansJournal of Molecular Medicine, 1984
- Pharmacokinetics of quinidine and three of its metabolites in manJournal of Pharmacokinetics and Biopharmaceutics, 1984
- Pharmacokinetics and metabolism of nifedipine.Hypertension, 1983
- Nifedipine Kinetics and Bioavailability After Single Intravenous and Oral Doses in Normal SubjectsThe Journal of Clinical Pharmacology, 1983
- Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoinJournal of Pharmacokinetics and Biopharmaceutics, 1980