RT Journal Article
SR Electronic
T1 Cationic Drug Pharmacokinetics in Diseased Livers Determined by Fibrosis Index, Hepatic Protein Content, Microsomal Activity, and Nature of Drug
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1079
OP 1087
DO 10.1124/jpet.301.3.1079
VO 301
IS 3
A1 Daniel Y. Hung
A1 Ping Chang
A1 Kee Cheung
A1 Brett McWhinney
A1 Paul P. Masci
A1 Michael Weiss
A1 Michael S. Roberts
YR 2002
UL http://jpet.aspetjournals.org/content/301/3/1079.abstract
AB 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 α1-acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (logPapp) 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), andkin/koutwere related to physicochemical properties of drug (logPapp 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. The American Society for Pharmacology and Experimental Therapeutics