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Vol. 301, Issue 3, 1079-1087, June 2002

Cationic Drug Pharmacokinetics in Diseased Livers Determined by Fibrosis Index, Hepatic Protein Content, Microsomal Activity, and Nature of Drug

Daniel Y. Hung, Ping Chang, Kee Cheung, Brett McWhinney, Paul P. Masci, Michael Weiss and Michael S. Roberts

Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia (D.Y.H., P.C., P.P.M., M.S.R.); Division of Chemical Pathology, Princess Alexandra Hospital, Woolloongabba, Australia (K.C., B.M.); and Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Germany (M.W.)

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl4)-induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha 1-acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log Papp) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl4-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (kin) and efflux rate constant (kout), and kin/kout were related to physicochemical properties of drug (log Papp or pKa) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

0022-3565/02/3013-1079$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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