Abstract
Hepatic uptake and efflux transporters govern the systemic and hepatic exposure of many drugs and metabolites. Enalapril is a pharmacologically inactive prodrug of enalaprilat. Following oral administration, enalapril is converted to enalaprilat in hepatocytes and undergoes translocation into the systemic circulation to exert its pharmacologic effect by inhibiting angiotensin-converting enzyme. Although the transport proteins governing hepatic uptake of enalapril and the biliary excretion of enalapril and enalaprilat are well established, it remains unknown how hepatically derived enalaprilat translocates across the basolateral membrane into the systemic circulation. In this study, the role of ATP-binding cassette transporters in the hepatic basolateral efflux of enalaprilat was investigated using membrane vesicles. ATP-dependent uptake of enalaprilat into vesicles expressing multidrug resistance–associated protein (MRP) 4 was significantly greater (∼3.8-fold) than in control vesicles. In contrast, enalaprilat was not transported to a significant extent by MRP3, and enalapril was not transported by either MRP3 or MRP4. The functional importance of MRP4 in the basolateral excretion of derived enalaprilat was evaluated using a novel basolateral efflux protocol developed in human sandwich-cultured hepatocytes. Under normal culture conditions, the mean intrinsic basolateral efflux clearance (CLint,basolateral) of enalaprilat was 0.026 ± 0.012 µl/min; enalaprilat CLint,basolateral was significantly reduced to 0.009 ± 0.009 µl/min by pretreatment with the pan-MRP inhibitor MK-571. Results suggest that hepatically derived enalaprilat is excreted across the hepatic basolateral membrane by MRP4. Changes in MRP4-mediated basolateral efflux may alter the systemic concentrations of this active metabolite, and potentially the efficacy of enalapril.
Footnotes
- Received February 20, 2014.
- Accepted June 23, 2014.
↵1 Current affiliation: Department of Drug Metabolism and Pharmacokinetics, Theravance Biopharma Inc., South San Francisco, California.
↵2 Current affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington.
This research was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM41935] (to K.L.R.B.); Deutsche Forschungsgemeinschaft grant [Ko4185/1-1] (to K.K.); and an Amgen Predoctoral Fellowship in Pharmacokinetics and Drug Disposition (to B.C.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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