title: Endotoxin does not alter the pharmacokinetics of micafungin, but it impairs biliary excretion of micafungin via multidrug resistance-associated protein 2 (ABCC2/Mrp2) in rats.
abstract: Micafungin, a newly developed echinocandin-type antifungal agent, is widely used for the treatment of deep-seated fungal infections including those of Candida species and Aspergillus species. In the present study, the possible alterations in the pharmacokinetics and biliary excretion of micafungin were investigated in endotoxemic rats induced by Klebsiella pneumoniae endotoxin. Endotoxin (2 mg/kg) was injected intraperitoneally 24 h before an intravenous injection of micafungin (1 mg/kg). No significant differences in the plasma concentration-time curves and pharmacokinetic parameters of micafungin were observed between endotoxin-treated and endotoxin-untreated rats. When endotoxin-treated rats received a constant-rate infusion of micafungin, the biliary clearance of micafungin was significantly decreased, whereas the steady-state plasma concentration did not change. By protein immunoblot analysis, a significant decrease in the expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2), which is an efflux protein for micafungin, was observed in endotoxin-treated rats. These results suggest that endotoxin-induced decrease in the hepatobiliary excretion of micafungin is caused, at least in part, by the reduction of Mrp2-mediated hepatobiliary transport ability. The present study may provide information suggesting that micafungin can be used for patients with endotoxemia without the need for dosage adjustment.
authors.affiliation: Department of Hospital Pharmacy and Pharmacokinetics, Aichi Medical University School of Medicine, Nagakute-cho, Aichi-gun, Aichi, 480-1195, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Noda
authors.forename: Fumie
authors.initials: F
authors.lastname: Abe
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Miki
authors.initials: M
authors.lastname: Kato
authors.forename: Miki
authors.initials: M
authors.lastname: Katoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
authors.forename: Hiroko
authors.initials: H
authors.lastname: Saito
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport; D054714:Echinocandins / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D019446:Endotoxemia / Q000188:drug therapy / Q000382:microbiology; D004731:Endotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D000077551:Micafungin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D054714:Echinocandins; D004731:Endotoxins; D055666:Lipopeptides; D000077551:Micafungin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins