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P-Glycoprotein Increases Portal Bioavailability of Loperamide in Mouse by Reducing First-Pass Intestinal Metabolism.

Drug Metab Dispos. 2013 Jan 3;

Authors: Dufek MB, Knight BM, Bridges AS, Thakker DR


P-glycoprotein (P-gp) and CYP3A/Cyp3a in the intestine can attenuate absorption of orally administered drugs. While some suggest that P-gp enhances intestinal metabolism by CYP3A/Cyp3a during absorption of a dual substrate, others suggest that P-gp reduces the metabolism in the intestine when substrates are at sub-saturating concentrations. Hence, to elucidate the cellular mechanisms that can address these divergent reports, we studied intestinal absorption of the dual substrate, loperamide, in portal vein-cannulated P-gp competent and P-gp deficient mice. These studies showed that at low doses of loperamide, which produced intestinal concentrations near the apparent K(m) for oxidative metabolism, the bioavailability across the intestine (F(G)) was 6-fold greater in the P-gp competent mice than in P-gp deficient mice. The higher F(G) of loperamide in the presence of P-gp was attributed to lower loperamide intestinal metabolism. However, at high doses of loperamide, the sparing of first-pass metabolism by P-gp was balanced against the attenuation of absorption by apical efflux, resulting in no net effect on F(G). In vitro studies with intestinal tissue from P-gp competent and deficient mice confirmed that P-gp reduced the metabolic rate of loperamide during absorptive flux at concentrations near Km but had little effect on metabolism at higher (saturating) concentrations. Further, studies in which Cyp3a was chemically inactivated by aminobenzotriazole (ABT) in P-gp competent and deficient mice, showed that P-gp and Cyp3a individually attenuated FG by 8-fold and 70-fold, respectively. These results confirmed that P-gp effectively protects loperamide at low doses from intestinal first-pass metabolism during intestinal absorption.

PMID: 23288866 [PubMed - as supplied by publisher]