Reduced elimination clearance of micafungin in rats with cholestatic hyperbilirubinemia.
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.
Konishi
Hiroki
H
Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan. konishih@osaka-ohtani.ac.jp
Fukushima
Keizo
K
Sudo
Masatomo
M
Sumi
Masaki
M
Minouchi
Tokuzo
T
Iga
Ikumi
I
Shibata
Nobuhito
N
Takada
Kanji
K
Yamaji
Akira
A
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D002779:Cholestasis / Q000097:blood / Q000150:complications* / Q000378:metabolism; D004195:Disease Models, Animal; D054714:Echinocandins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006932:Hyperbilirubinemia / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D007275:Injections, Intravenous; D055666:Lipopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D000077551:Micafungin; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin; D001663:Bilirubin