title: Inhibition of the multidrug efflux pump in isolated hepatocyte couplets by immunosuppressants FK506 and cyclosporine.
abstract: Fluorescence image analysis of isolated rat hepatocyte couplets, which retain a bile canaliculus between them, has shown the presence of transport systems for the bile acid and non-bile acid organic anion in the canalicular membrane. The cells also transported Fura-2 and BCECF, which are fluorescent indicators of intracellular Ca2+ and H+ concentrations, respectively, into the canaliculus. Both Fura-2 and BCECF transports were inhibited by progesterone, verapamil, vinblastine, and daunomycin, indicating that the transports are due to a multidrug efflux pump (P-glycoprotein) in the canalicular membrane. Interestingly, the transport by the multidrug efflux pump was inhibited by immunosuppressants FK506 (tacrolimus) and cyclosporine, their half-maximal inhibitory concentrations in the cell suspension being 10 microM and 0.6 microM, respectively. In contrast, the reported immunosuppressive potency of FK506 is 10- to 100-fold that of cyclosporine. Inhibition by immunosuppressants of the multidrug efflux pump, which is a transporter of cytotoxic and other drugs and present in normal human tissues--such as kidney, liver, the blood-brain barrier, and colon--may, at least partly, explain side effects caused by cyclosporine in these tissues of transplant recipients. FK506 at its clinical concentrations may not inhibit the multidrug efflux pump.
authors.affiliation: Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takeguchi
authors.forename: K
authors.initials: K
authors.lastname: Ichimura
authors.forename: M
authors.initials: M
authors.lastname: Koike
authors.forename: W
authors.initials: W
authors.lastname: Matsui
authors.forename: T
authors.initials: T
authors.lastname: Kashiwagura
authors.forename: K
authors.initials: K
authors.lastname: Kawahara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001648:Bile Canaliculi / Q000648:ultrastructure; D016572:Cyclosporine / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005452:Fluoresceins; D005456:Fluorescent Dyes; D016257:Fura-2; D008099:Liver / Q000166:cytology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008856:Microscopy, Fluorescence / Q000379:methods; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D012815:Signal Processing, Computer-Assisted; D016559:Tacrolimus / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008562:Membrane Glycoproteins; D011374:Progesterone; D014747:Vinblastine; D016572:Cyclosporine; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; D014700:Verapamil; D016257:Fura-2; D016559:Tacrolimus; D003630:Daunorubicin