Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug.
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 (CCl(4))-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 P(app)) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl(4)-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 (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P(app) or pK(a)) 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.
Hung
Daniel Y
DY
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
Chang
Ping
P
Cheung
Kee
K
McWhinney
Brett
B
Masci
Paul P
PP
Weiss
Michael
M
Roberts
Michael S
MS
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002412:Cations / Q000493:pharmacokinetics; D002492:Central Nervous System Depressants / Q000009:adverse effects; D000431:Ethanol / Q000009:adverse effects; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009961:Orosomucoid; D004364:Pharmaceutical Preparations / Q000145:classification / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D002412:Cations; D002492:Central Nervous System Depressants; D009961:Orosomucoid; D004364:Pharmaceutical Preparations; D011506:Proteins; D000431:Ethanol