Contributions of transporter on pharmacokinetics of new drug candidates

摘要

Hepatobiliary transport of three new drug candidates were investigated to evaluate the contributioin 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 neutral indolocarbazole anticancer agent.In rats,all three compounds were excreted predominntly 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#mu7#M and Vmax values of 517,564 and 1600pmol/min/10~6 cells,respectively.The uptake was ATP-dependent for Compounds A and B are analogous judging from their inhibition profile by various compounds.Compounds A and B were take up into rat canalicular membrane vesicles (CMV)in an ATP-dependent manner.Contributiion 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.