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Department of Pharmaceutical Sciences, Faculty of Pharmacy (L.L., K.S.P.), and Department of Pharmacology, Faculty of Medicine (K.S.P.), University of Toronto, Toronto, Ontario, Canada
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.
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