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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  • Uesugi Miwa
    Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital Department of Pharmacy, Kyoto University Hospital
  • Hosokawa Mio
    Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
  • Shinke Haruka
    Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
  • Hashimoto Emina
    Department of Pharmacy, Kyoto University Hospital
  • Takahashi Tamotsu
    Department of Pharmacy, Kyoto University Hospital
  • Kawai Tomoki
    Department of Pharmacy, Kyoto University Hospital
  • Matsubara Kazuo
    Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital Department of Pharmacy, Kyoto University Hospital
  • Ogawa Kohei
    Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
  • Fujimoto Yasuhiro
    Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
  • Okamoto Shinya
    Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
  • Kaido Toshimi
    Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
  • Uemoto Shinji
    Division of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Hospital
  • Masuda Satohiro
    Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital Department of Pharmacy, Kyoto University Hospital

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タイトル別名
  • Influence of Cytochrome P450 (CYP) <i>3A4*1G</i> 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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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.

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