title: In vitro investigation of the hepatobiliary disposition mechanisms of the antifungal agent micafungin in humans and rats.
abstract: The purpose of the present study was to elucidate the transport mechanisms responsible for elimination of micafungin, a new semisynthetic 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 primarily (∼75%) by transporter-mediated mechanisms in rat and human. Micafungin uptake into hepatocytes was inhibited by taurocholate (K(i) = 61 μM), Na(+) depletion (45-55% reduced), and 10 μM rifampin (20-25% reduced); these observations support the involvement of Na(+)-taurocholate-cotransporting polypeptide (NTCP/Ntcp) and, to a lesser extent, organic anion-transporting polypeptides in the hepatic uptake of micafungin. The in vitro biliary clearance of micafungin, as measured by the B-CLEAR technique, 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% in the presence of the bile salt export pump (BSEP) inhibitors taurocholate (100 μM) and nefazodone (25 μM), respectively. Biliary excretion of micafungin also was reduced in the presence of breast cancer resistance protein inhibitors [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (10 μM) and fumitremorgin C (10 μM)]. In vitro biliary excretion of micafungin was not significantly altered by coincubation with P-glycoprotein or multidrug resistance-associated protein 2 inhibitors. These results suggest that NTCP/Ntcp and BSEP/Bsep are primarily responsible for hepatobiliary disposition of micafungin in human and rat. Interference with hepatic bile acid disposition could be one mechanism underlying hepatotoxicity associated with micafungin in some patients.
authors.affiliation: Department of Pharmaceutical Sciences, Katholieke Universiteit Leuven, O&N2, Herestraat 49, Leuven, Belgium.
authors.forename: Souzan B
authors.initials: SB
authors.lastname: Yanni
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Augustijns
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.forename: Dhiren R
authors.initials: DR
authors.lastname: Thakker
authors.forename: Pieter P
authors.initials: PP
authors.lastname: Annaert
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001648:Bile Canaliculi / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000378:metabolism / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D055666:Lipopeptides / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D000077551:Micafungin; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D000077551:Micafungin