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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 1079-1087; DOI: https://doi.org/10.1124/jpet.301.3.1079
Daniel Y. Hung
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Ping Chang
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Kee Cheung
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Brett McWhinney
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Paul P. Masci
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Michael Weiss
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Michael S. Roberts
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1079-1087; DOI: https://doi.org/10.1124/jpet.301.3.1079

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1079-1087; DOI: https://doi.org/10.1124/jpet.301.3.1079
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