Fukudo Masahide, Yano Ikuko, Yoshimura Atsushi, Masuda Satohiro, Uesugi Miwa, Hosohata Keiko, Katsura Toshiya, Ogura Yasuhiro, Oike Fumitaka, Takada Yasutsugu, Uemoto Shinji, Inui Ken-ichi
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto, Japan.
Pharmacogenet Genomics. 2008 May;18(5):413-23. doi: 10.1097/FPC.0b013e3282f9ac01.
The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype.
Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5*3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program.
CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A51 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17-1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A53/*3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan-Meier method, was significantly associated with the recipient's but not donor's CYP3A5 genotype (*1/*1 and *1/*3 vs. *3/*3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81).
These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.
研究多药耐药1（MDR1）基因以及细胞色素P450（CYP）基因CYP3A4和CYP3A5对成人活体肝移植受者他克莫司口服清除率（CL/F）的潜在影响。此外，分析了与CYP3A5基因型相关的肾功能障碍的发生情况。
本研究纳入了60例接受他克莫司治疗的初治成人肝移植患者。使用非线性混合效应建模程序研究了各种协变量（包括移植时采集的每个组织中测量的MDR1和CYP3A4的肠道和肝脏mRNA水平，以及CYP3A5*3多态性）对术后前50天CL/F的影响。
CL/F在术后第14天之前呈线性增加，此后达到稳定状态。肝移植后立即的初始CL/F受肠道MDR1 mRNA水平的显著影响（P<0.005）。此外，在天然肠道而非移植肝脏中携带CYP3A51等位基因的患者，其CL/F随时间的恢复比具有肠道CYP3A53/*3基因型的患者高1.47倍（95%置信区间，1.17 - 1.77倍，P<0.005）。通过Kaplan-Meier方法评估，移植后1年内肾功能障碍的累积发生率与受者而非供者的CYP3A5基因型显著相关（*1/1和1/3与3/*3相比：受者，17%对46%，P<0.05；供者，35%对38%，P = 0.81）。
这些发现表明，CYP3A5*1基因型以及肠细胞中的MDR1 mRNA水平促成了成人活体肝移植术后早期受者他克莫司CL/F的个体间差异。此外，肾脏中的CYP3A5可能在他克莫司相关肾毒性的发生中起保护作用。
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