Association between <i>CYP3A5</i> Genotypes in Graft Liver and Increase in Tacrolimus Biotransformation from Steroid Treatment in Living-donor Liver Transplant Patients
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- HOSOHATA Keiko
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
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- UESUGI Miwa
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
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- HASHI Sachiyo
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
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- HOSOKAWA Mio
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
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- INUI Ken-ichi
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
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- MATSUBARA Kazuo
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
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- OGAWA Kohei
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University
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- FUJIMOTO Yasuhiro
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University
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- KAIDO Toshimi
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University
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- UEMOTO Shinji
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University
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- MASUDA Satohiro
- Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital
Bibliographic Information
- Other Title
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- Association between CYP3A5 Genotypes in Graft Liver and Increase in Tacrolimus Biotransformation from Steroid Treatment in Living-donor Liver Transplant Patients
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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.<br>
Journal
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- Drug Metabolism and Pharmacokinetics
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Drug Metabolism and Pharmacokinetics 29 (1), 83-89, 2014
The Japanese Society for the Study of Xenobiotics
