Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
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Required Transient Dose Escalation of Tacrolimus in Living-Donor Liver Transplant Recipients with High Concentrations of a Minor Metabolite M-II in Bile
Masahiro SHIMOMURASatohiro MASUDAMaki GOTOToshiya KATSURATetsuya KIUCHIYasuhiro OGURAFumitaka OIKEYasutsugu TAKADAShinji UEMOTOKen-ichi INUI
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2008 Volume 23 Issue 5 Pages 313-317


  The profiles of tacrolimus metabolites in the whole blood and bile were examined in two living-donor liver transplant patients, who transiently required higher doses of tacrolimus. Even when the 16 mg/day or oral 10 mg/day and intravenous infusion of 0.5 mg/day of tacrolimus were administered, its trough level in each patient did not reach over 15 ng/mL. By use of liquid chromatography-tandem mass spectrometry/mass spectrometry methods, a minor metabolite M-II was found to be a major metabolite both in blood and bile in these cases. However, a primary metabolite M-I was confirmed as the majority in the bile of other 8 control cases. Each graft liver and native intestine carried CYP3A5*1/*3 or *3/*3 and *1/*3 or *1/*3, respectively. Therefore, the CYP3A5 genotype could not explain the present phenomena. After removing the bile drainage tube to allow the bile flow into intestine, the required doses of tacrolimus were decreased to around 20% compared to each maximum dosage. In conclusion, a minor metabolite M-II was first found in the human bile, suggesting that the appearance of M-II in bile could associate with the extensive metabolism of tacrolimus and/or the requirement of larger oral dosage.

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© 2008 by The Japanese Society for the Study of Xenobiotics
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