Influence of Cytochrome P450 (CYP) 3A4*1G Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients
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概要
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Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1–14; p<0.001, postoperative days 15–35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.
- 公益社団法人 日本薬学会の論文
著者
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MATSUBARA Kazuo
Department of Hospital Pharmacy & Pharmacology,Asahikawa Medical College,Japan
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Ogawa Kohei
Division Of Hepato-biliary-pancreatic Surgery And Transplantation Department Of Surgery Kyoto Univer
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Uemoto Shinji
Division Of Hepato-biliary-pancreatic Surgery And Transplantation Department Of Surgery Kyoto Univer
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Okamoto Shinya
Division Of Internal Medicine Nabari City Hospital
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TAKAHASHI Tamotsu
Department of Applied Chemistry, Faculty of Engineering, Oita University
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Masuda Satohiro
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
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Shinke Haruka
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
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Fujimoto Yasuhiro
Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
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Uesugi Miwa
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
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Hosokawa Mio
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
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Hashimoto Emina
Department of Pharmacy, Kyoto University Hospital
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Kawai Tomoki
Department of Pharmacy, Kyoto University Hospital
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Kaido Toshimi
Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
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Matsubara Kazuo
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
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Ogawa Kohei
Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
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Takahashi Tamotsu
Department of Pharmacy, Kyoto University Hospital
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Okamoto Shinya
Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
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