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Article CommentaryCommentary

THE ROLES OF TRANSPORTERS AND ENZYMES IN HEPATIC DRUG PROCESSING

Lichuan Liu and K. Sandy Pang
Drug Metabolism and Disposition January 2005, 33 (1) 1-9; DOI: https://doi.org/10.1124/dmd.104.001149
Lichuan Liu
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K. Sandy Pang
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Abstract

A simple, physiological model was used to illustrate the competing nature of transporters and metabolic enzymes in hepatic drug processing. Enalapril, a drug whose basolateral influx and canalicular efflux are mediated by rat organic anion-transporting polypeptide 1 (Oatp1) and rat multidrug resistance-associated protein 2 (Mrp2), respectively, and metabolism by the carboxylesterases, was enlisted as the example to illustrate how the transport and intrinsic clearances are inter-related in the estimation of the hepatic and metabolic, and excretion clearances. Moreover, simulations were performed to explore the effects of inhibitors or inducers of transporters/enzymes to unravel the compensatory changes of alternate pathways. Generally speaking, inhibition of one pathway led to an apparent increase in the alternate (competing) pathway and total hepatic clearance was decreased; induction would lead to an apparent decrease in the alternate pathway and an increase in total hepatic clearance. A reduction in influx clearance brought about parallel decreases in the biliary and metabolic clearances, whereas a reduction in efflux basolateral clearance evoked similar increases in biliary and metabolic clearances. However, the steady-state tissue concentration (CL,ss) or area under the tissue concentration-time curve (AUCL) was reliant only on the unbound fraction in liver, and the secretory and metabolic intrinsic clearances and not the influx and efflux clearances. Variations in the influx and efflux intrinsic clearances evoked temporal changes in the tissue concentration-time profile but not the AUCL or CL,ss. The pharmacokinetic theory developed offers data interpretation from literature reports on P-glycoprotein and cytochrome P450 substrates with mdr1a/1b knockout versus wild-type mice, and rat liver perfusion studies, with and without the use of inhibitors. In some cases, critiques on data interpretation were made.

Footnotes

  • This work was supported by the Canadian Institutes for Health Research, MOP65417.

  • doi:10.1124/dmd.104.001149.

  • ABBREVIATIONS: Oatp, rat organic anion-transporting polypeptide; Mrp2, rat multidrug resistance-associated protein 2; Cyp3a, rat cytochrome P450 3a subfamily; AUC, area under the blood concentration-time curve; AUCL, area under the liver tissue concentration-time curve; CLint,sec, secretory intrinsic clearance; CLint,met, metabolic intrinsic clearance; CLliver,tot, total hepatic clearance; CLliver,ex, biliary clearance; CLliver,met, hepatic metabolic clearance; PXR, pregnane X receptor; Pgp, P-glycoprotein; FK506, tacrolimus; KO, knockout mouse; GG918, N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine.

    • Received June 21, 2004.
    • Accepted September 28, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (1)
Drug Metabolism and Disposition
Vol. 33, Issue 1
1 Jan 2005
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Article CommentaryCommentary

THE ROLES OF TRANSPORTERS AND ENZYMES IN HEPATIC DRUG PROCESSING

Lichuan Liu and K. Sandy Pang
Drug Metabolism and Disposition January 1, 2005, 33 (1) 1-9; DOI: https://doi.org/10.1124/dmd.104.001149

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Article CommentaryCommentary

THE ROLES OF TRANSPORTERS AND ENZYMES IN HEPATIC DRUG PROCESSING

Lichuan Liu and K. Sandy Pang
Drug Metabolism and Disposition January 1, 2005, 33 (1) 1-9; DOI: https://doi.org/10.1124/dmd.104.001149
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  • Article
    • Abstract
    • Theory
    • Improved CLefflux, CLint,sec, and CLint,met Estimates for Physiological Modeling
    • Dynamics of Secretory and Metabolic Intrinsic Clearances and Basolateral Influx and Efflux Clearances on Hepatic Metabolic and Excretory Clearances
    • Liver Tissue Concentration Profiles
    • Effects of the Secretion, the Influx and Efflux Clearances, and Saturable Metabolism on Hepatic Clearance and Metabolite Formation
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