Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918.
The disposition of tacrolimus and the influence of cyclosporine, troleandomycin, and GF120918 (GG918, or N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine) on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner following a bolus dose of tacrolimus (100 microg), a substrate for P-glycoprotein (P-gp) and CYP3A, or with felodipine (200 microg), a substrate only for CYP3A. Perfusions of each substrate were also examined in groups of rats in the presence of the inhibitors: troleandomycin (20 microM, CYP3A inhibitor), GG918 (1 microM, P-gp inhibitor), or cyclosporine (10 microM, CYP3A and P-gp inhibitor). In all experiments, perfusate and bile were collected for 60 min. Tacrolimus, felodipine, and their primary metabolites were determined in perfusate and bile by liquid chromatography/tandem mass spectrometry. The area under the curve (AUC) from 0 to 30 min was determined. For the dual CYP3A and P-gp substrate, tacrolimus, AUC +/- S.D. was decreased from control (2,260 +/- 430 ng. min/ml) by GG918 (1,730 +/- 270 ng. min/ml, P < 0.05) and was increased by troleandomycin (5,200 +/- 2,470 ng. min/ml, P < 0.05) and cyclosporine (4,390 +/- 2,080 ng. min/ml, P < 0.05). For the exclusive CYP3A substrate, felodipine, AUC was unchanged from control by GG918 but increased by troleandomycin and cyclosporine. It is concluded that GG918 increased the hepatic exposure of tacrolimus by inhibiting the canalicular P-gp transport, whereas GG918 has no effect on hepatic disposition of felodipine. These results support our hypothesis that the hepatic metabolic clearance of a dual substrate will be increased by inhibiting the efflux transporter.
Department of Biopharmaceutical Sciences, University of California San Francisco, 533 Parnassus, Room U-68, San Francisco, CA 94143-0446, USA.
Chi-Yuan
CY
Wu
Leslie Z
LZ
Benet
D000166:Acridines / Q000493:pharmacokinetics*; D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004347:Drug Interactions; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics*; D014217:Troleandomycin / Q000493:pharmacokinetics*
D000166:Acridines; D044005:Tetrahydroisoquinolines; D016572:Cyclosporine; D014217:Troleandomycin; C083501:Elacridar; D016559:Tacrolimus