CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation
CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation
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DOI：
10.1097/01.fpc.0000114747.08559.49
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发表时间：
2004-07-01
期刊：
影响因子：
--
通讯作者：
Inui, K
中科院分区：
文献类型：
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作者：
Goto, M;Masuda, S;Inui, K
目的他克莫司广泛应用于器官移植术后的免疫抑制治疗，但其药代动力学个体差异大，血药浓度难以控制。我们以前曾报道，肠P-糖蛋白（MDR 1）作为吸收屏障有助于这种变化，但肝脏代谢的作用尚不清楚。方法在本研究中，我们评估了供者和受者的MDR 1和细胞色素P450（CYP）3A基因型，以及基因多态性对活体肝移植（LDLT）受体mRNA表达和他克莫司浓度/剂量（C/D）比值的影响结果MDR 1 C3435 T和G2677 T/A均不影响MDR 1表达水平和他克莫司C/D比值。CYP 3A 4 *1B基因型未检出，CYP 3A 5 *3基因型的等位基因频率为76.3%。*3/*3基因型使CYP 3A 5的mRNA水平显著降低，携带CYP 3A 5 *1/*1基因型的部分肝移植受体的他克莫司C/D比值降低。结合肠道MDR 1水平和肝脏CYP 3A 5基因型分析，发现无论CYP 3A 5基因型如何，术后第1周MDR 1水平高的患者他克莫司C/D比值均较低。结论LDLT受者第1周他克莫司的药代动力学受肠道P-糖蛋白通量的影响;之后，主要是肝脏代谢促进他克莫司的排泄，CYP 3A 5 *1/*1基因型携带者需要高剂量的他克莫司以达到目标浓度。(C)2004年利平科特威廉姆斯威尔金斯。
Objectives Tacrolimus is widely used for immunosuppressive therapy after organ transplantation, but its pharmacokinetics shows such great interindividual variation that control of its blood concentration is difficult. We have previously reported that an intestinal P-glycoprotein (MDR1) contributes to this variation as an absorptive barrier, but the role of hepatic metabolism is not clear.Methods In this study, we have evaluated the genotypes of MDR1 and cytochrome P450 (CYP) 3A in donor and recipient, and the influence of polymorphisms on mRNA expression and the tacrolimus concentration/dose (C/D) ratio in recipients of living-donor liver transplantation (LDLT).Results The expression level of MDR1 and tacrolimus C/D ratio were not affected by either MDR1 C3435T or G2677T/A. The CYP3A4*1B genotype was not detected, but the CYP3A5*3 genotype had an allelic frequency of 76.3%. The mRNA level of CYP3A5 was significantly reduced by the *3/*3 genotype, and the tacrolimus C/D ratio was decreased in recipients engrafted with partial liver carrying CYP3A5*1/*1 genotype. An analysis of the combination of intestinal MDR1 level and liver CYP3A5 genotype revealed that the tacrolimus C/D ratio was lower in the group with higher MDR1 levels regardless of CYP3A5 genotype during postoperative week 1.Conclusions These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration. (C) 2004 Lippincott Williams Wilkins.