title: The impact of P-glycoprotein efflux on enterocyte residence time and enterocyte-based metabolism of verapamil.
abstract: P-glycoprotein (P-gp) can limit the intestinal permeability of a number of compounds and may therefore influence their exposure to metabolizing enzymes within the enterocyte (e.g. cytochrome P450 3A, CYP 3A). In this study, the intestinal metabolic profile of verapamil, the influence of P-gp anti-transport on the cellular residence time of verapamil, and the impact of this change in residence time on the extent of enterocyte-based metabolism have been investigated in-vitro, utilizing segments of rat jejunum and side-by-side diffusion chambers. Verapamil exhibited concentration-dependent P-gp efflux and CYP 3A metabolism. The P-gp efflux of verapamil (1 microM) increased the cellular residence time across the intestinal membrane (approximately 3-fold) in the mucosal to serosal (m to s) direction relative to serosal to mucosal (s to m), yielding significantly greater metabolism (approximately 2-fold), presumably as a result of the prolonged exposure to CYP 3A. Intestinal metabolism of verapamil generated not only norverapamil, but resulted also in the formation of an N-dealkylated product (D-617). Norverapamil and D-617 accumulated significantly in mucosal chambers, relative to serosal chambers, over the time course of the experiment. Based on these in-vitro data, it was apparent that P-gp efflux prolonged the cellular residence time of verapamil (m to s) and therefore increased the extent of intestinal metabolism, and also played a role in metabolite secretion from within the enterocyte.
authors.affiliation: Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Melbourne, Australia.
authors.forename: B M
authors.initials: BM
authors.lastname: Johnson
authors.forename: W N
authors.initials: WN
authors.lastname: Charman
authors.forename: C J
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002121:Calcium Channel Blockers / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D020895:Enterocytes / Q000378:metabolism*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014700:Verapamil / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating