James Brian Houston

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The accuracy of in vitro inhibition parameters in scaling to in vivo drug-drug interactions (DDI) was examined for over 40 drugs using seven human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C(max), estimated hepatic inlet C(max), fraction unbound, and fraction of the probe drug(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)
This review brings you up-to-date with the hepatocyte research on: 1) in vitro-in vivo correlations of metabolism and clearance; 2) CYP enzyme induction, regulation, and cross-talk using human hepatocytes and hepatocyte-like cell lines; 3) the function and regulation of hepatic transporters and models used to elucidate their role in drug clearance; 4)(More)
The issue of drug–drug interactions has generated significant concern within the pharmaceutical industry and among regulatory authorities in recent years. This has arisen with respect to early termination of clinical development (e.g. furafylline), refusal of approval (e.g. mibefradil in Sweden), severe prescribing restrictions and withdrawal from the(More)
The glucuronidation kinetics of the prototypic substrates 4-methylumbelliferone (4MU) and 1-naphthol (1NP) by human UDP-glucuronosyltransferases (UGT) 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17 were investigated. Where activity was demonstrated, inhibitory effects of diclofenac, probenecid, and the solvents acetone, acetonitrile, dimethyl(More)
The aim of this study is to compare the accuracy of five methods for predicting in vivo intrinsic clearance (CLint) and seven for predicting hepatic clearance (CLh) in humans using in vitro microsomal data and/or preclinical animal data. The human CLint was predicted for 33 drugs by five methods that used either in vitro data with a physiologic scaling(More)
Reported predictions of human in vivo hepatic clearance from in vitro data have used a variety of values for the scaling factors human microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of liver, generally with no consideration of the extent of their inter-individual variability. We have collated and analysed data from a number of sources, to(More)
Human liver microsomes have typically resulted in marked underprediction of in vivo human intrinsic clearance (CL(int)); therefore, the utility of cryopreserved hepatocytes as an alternative in vitro system has become an important issue. In this study, 10 compounds (tolbutamide, diclofenac, S-warfarin, S-mephenytoin, dextromethorphan, bufuralol, quinidine,(More)
In recent years the phenomenon of hepatic microsomal nonspecific binding of drugs has received considerable attention in this journal, as well as in others. There is general agreement on the need to correct kinetic constants (namely, Km and Ki values) for the fraction of drug concentration unbound (fuinc) to ensure optimal prediction of clearance and(More)