title: Association between CYP3A5 genotypes in graft liver and increase in tacrolimus biotransformation from steroid treatment in living-donor liver transplant patients.
abstract: We retrospectively examined whether cytochrome P450 (CYP) 3A5 genotypes are associated with high-dose steroid pulse treatment-induced functional gain of tacrolimus biotransformation in living-donor liver transplant patients. Concentrations of tacrolimus and its 3 primary metabolites, 13-O-demethyl tacrolimus (M-I), 31-O-demethyl tacrolimus (M-II), and 15-O-demethyl tacrolimus (M-III), were measured in trough blood samples from 18 liver transplant patients, by liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS). In patients engrafted with a CYP3A5*1-carrying liver but not with a CYP3A5*3/*3-carrying liver, the concentration/dose ratio of tacrolimus significantly fell after therapy, while ratios of M-I/tacrolimus, M-II/tacrolimus, and M-III/tacrolimus were significantly higher after therapy than before (p = 0.032, p = 0.023, and p = 0.0078, respectively). After steroid pulse therapy, the concentration of tacrolimus measured by immunoassay was significantly higher than that measured by LC-MS/MS in patients engrafted with a CYP3A5*1-carrying liver, but not those engrafted with a CYP3A5*3/*3-carrying liver. This suggests that the increased ratio of tacrolimus metabolites/tacrolimus can be explained by induction of CYP3A5 via high-dose steroid pulse therapy. Further, the concentrations of tacrolimus measured by the immunoassays were overestimated, partly because of cross-reactivity of the monoclonal antibody they incorporated to detect tacrolimus, with the increased metabolites in patients with a CYP3A5*1-carrying graft liver.
authors: Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital.
authors: Keiko
authors: K
authors: Hosohata
authors: Miwa
authors: M
authors: Uesugi
authors: Sachiyo
authors: S
authors: Hashi
authors: Mio
authors: M
authors: Hosokawa
authors: Ken-Ichi
authors: K
authors: Inui
authors: Kazuo
authors: K
authors: Matsubara
authors: Kohei
authors: K
authors: Ogawa
authors: Yasuhiro
authors: Y
authors: Fujimoto
authors: Toshimi
authors: T
authors: Kaido
authors: Shinji
authors: S
authors: Uemoto
authors: Satohiro
authors: S
authors: Masuda
mesh_terms: D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005838:Genotype; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007118:Immunoassay; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007223:Infant; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D020551:Pulse Therapy, Drug; D012189:Retrospective Studies; D013256:Steroids / Q000008:administration & dosage / Q000494:pharmacology*; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry
chemical_list: D007166:Immunosuppressive Agents; D013256:Steroids; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus