Abstract
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.
Footnotes
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This study was supported by the National Health and Medical Research Council of Australia and the Queensland and New South Wales Lions Kidney and Medical Research Foundation. The results for normal control groups (all data sets) were obtained from Hung et al. (2001), published in J Pharmacol Exp Ther297:780–789.
- Abbreviations:
- MID
- multiple indicator dilution technique
- AAG
- α1-acid glycoprotein
- CCl4
- carbon tetrachloride
- CLint
- intrinsic elimination clearance
- P450
- cytochrome P450
- E
- hepatic extraction ratio
- F
- availability
- FI
- fibrosis index
- MP
- microsomal protein
- MT
- mean transit time
- PS
- permeability-surface area product
- AST
- serum aspartate aminotransferase
- ALT
- alanine aminotransferase
- MOPS
- 4-morpholinepropanesulfonic acid
- HPLC
- high- performance liquid chromatography
- CR
- cytoskeleton residue
- CV2
- normalized variance
- Received November 2, 2001.
- Accepted February 12, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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