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Reduced elimination clearance of micafungin in rats with cholestatic hyperbilirubinemia
Author(s) -
Konishi Hiroki,
Fukushima Keizo,
Sudo Masatomo,
Sumi Masaki,
Minouchi Tokuzo,
Iga Ikumi,
Shibata Nobuhito,
Takada Kanji,
Yamaji Akira
Publication year - 2010
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2009.00785.x
Subject(s) - micafungin , pharmacokinetics , medicine , bilirubin , endocrinology , volume of distribution , cholestasis , chemistry , clearance rate , clearance , antifungal , urology , amphotericin b , dermatology
We examined whether the pharmacokinetic disposition of micafungin (MCFG), an echinocandin class antifungal agent, is altered in hyperbilirubinemia using a rat model prepared by bile duct ligation (BDL). Serum bilirubin levels were increased depending upon the duration of BDL. The elimination rate constant and total body clearance (CL tot ) of MCFG were reduced by 24% and 16%, respectively, after BDL for 1 h, but there was no significant change in the apparent volume of distribution at steady‐state. The degree of reduction in the CL tot was much greater 7 days after BDL as compared with that 1 h after BDL (44% vs. 16%). However, the proportion of the biliary clearance in the CL tot was about 10%. This is similar to the extent of decrease in the CL tot by occlusion of the bile duct, demonstrating that decreased biliary excretion of MCFG makes only a minor contribution to its pharmacokinetic change. These findings suggest that the metabolic capacity of MCFG is markedly impaired in hepatic hypofunction secondary to hyperbilirubinemia, providing a fundamental explanation for the previous clinical report that there is a significant correlation between dose‐adjusted plasma MCFG concentration and serum bilirubin levels.