title: Required transient dose escalation of tacrolimus in living-donor liver transplant recipients with high concentrations of a minor metabolite M-II in bile.
abstract: 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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shimomura
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Maki
authors.initials: M
authors.lastname: Goto
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kiuchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oike
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Takada
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D001646:Bile / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D045162:Thiazolidinediones / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; C510846:M-II compound; D045162:Thiazolidinediones; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus