2001 Volume 16 Issue supplement Pages 108-109
Hepatobiliary transport of three new drug candidates were investigated to evaluate the contribution of membrane transporters on their pharmacokinetics. Compound A is an anionic cyclopentapeptide endothelin receptor antagonist, Compound B is an anionic endothelin antagonist (non-peptide), and Compound C is a neutral indolocarbazole anticancer agent. In rats, all three compounds were excreted predominantly into bile without oxidative metabolism. Compounds A, B and C were taken up extensively by isolated rat hepatocytes with Km values of 9.5, 5.7 and 8.9 μM and Vmax values of 517, 564 and 1600 pmol/min/106cells, respectively. The uptake was ATP-dependent for Compounds A and B but not for C. In spite of discrete chemical structures, uptake mechanisms of Compounds A and B are analogous judging from their inhibition profile by various compounds. Compounds A and B were taken up into rat canalicular membrane vesicles (CMV) in an ATP-dependent manner. Contribution of cMOAT (MRP2/ABCC2) is important for canalicular transport of Compounds A and B because their ATP-dependent uptakes into CMV prepared from EHBR were insignificant.
