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Received for publication June 22, 2004.
Revised September 8, 2004.
Accepted for publication September 28, 2004.
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 Oatp1 and Mrp2, respectively, and metabolism by the carboxylesterases, was enlisted as the example to illustrate how the transport and intrinsic clearances are inter-related in estimation of the hepatic and metabolic, and excretion clearances. Moreover, simulations were performed to explore the effects of inhibitors or inducers of transporter/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 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. The steady-state tissue concentration (Css) or area under the tissue concentration-time curve (AUCL), however, was reliant only on the secretory and metabolic intrinsic clearances and not the influx and efflux clearances. Variations in the metabolic or secretory intrinsic clearances evoked temporal changes in the concentration-time profile but not the AUCL or Css. The pharmacokinetic theory developed offers data interpretation from literature reports on P-glycoprotein and P450 substrates with mdr1a/1b knockout versus wild-type mice, and rat liver perfusion studies, with and without use of inhibitors. In some cases, critiques on data interpretation were made.
Key words:
ABC transporters, drug clearance, drug efflux, drug transport, enzyme kinetics, hepatobiliary transport, p-glycoprotein, pharmacokinetics, physiologically-based modeling, physiologically-based pharmacokinetics
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