American Society for Pharmacology and Experimental Therapeutics
Drug Metabolism and Disposition vol:38 issue:10 pages:1848-1856
The purpose of the present study was to better understand the mechanisms responsible for elimination of micafungin, a new semi-synthetic echinocandin antifungal agent, which is predominantly cleared by biliary excretion in humans and rats. In vitro studies using sandwich cultured rat and human hepatocytes were conducted. Micafungin uptake occurred mainly (~75%) by transporter-mediated mechanisms in rat and human. Total accumulation clearance values were about 24 and 19 µL/min/mg protein in human and rat hepatocytes, respectively. Micafungin uptake into hepatocytes was inhibited by taurocholate (IC50 = 73.7 µM) and Na-depletion (45-55%), as well as by 10 µM rifampicin (20-25%), supporting the involvement of Na+-taurocholate co-transporting peptide (NTCP, Ntcp) and to less extent organic anion transporting polypeptide (OATP, Oatp). The in vitro biliary clearance (Clbiliary) of micafungin amounted to 14 and 19 µL/min/mg protein in human and rat, respectively. In vitro biliary excretion of micafungin was reduced by 80 % and 75 %, respectively, in the presence of the bile salt export pump (BSEP) inhibitors taurocholate (100 µM) and nefazodone (25 µM), and to a less extent in the presence of breast cancer resistance protein (BCRP) inhibitors [GF918 (10 µM) and fumitremorgin C (10 µM)]. Co-incubation with P-glycoprotein or multidrug resistance associated protein 2 (MRP2) inhibitors did not significantly alter micafungin in vitro biliary excretion. The results suggest that primarily NTCP/Ntcp and BSEP/Bsep mediate hepatobiliary disposition of micafungin in human and rat.