Wei-lin Wang, Jing Jin, Shu-sen Zheng, Li-hua Wu, Ting-bo Liang, Song-feng Yu, Sheng Yan
Department of Hepatobiliary Pancreatic Surgery, Key Lab of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital of Medical College, Zhejiang University, Hang Zhou, People's Republic of China.
Liver Transpl. 2006 May;12(5):775-80. doi: 10.1002/lt.20709.
The aim of this study was to investigate whether the heterogeneity in tacrolimus dose requirement is associated with ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients during the first month after transplantation. ABCB1 and CYP3A5 genotyping was performed using the polymerase chain reaction restriction sites polymorphism-based procedure in Chinese liver transplant recipients (n = 50) and their corresponding donors (n = 50). Tacrolimus whole-blood trough concentrations were measured by immunoassays on the IMx analyzers (Abbott Diagnostics Laboratories, Abbott-Park, IL). Doses required to achieve target blood concentrations and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) were compared among patients according to allelic status of ABCB1 and CYP3A5. The ABCB1 3435CC was observed in 23 subjects (23%), whereas 64 (64%) carried 3435CT and 13 (13%) carried 3435TT. The CYP3A5*1/*1 was observed in 13 subjects (13%), 50 (50%) carried *1/3, and 37 (37%) carried3/3. The tacrolimus C/D ratios were obviously lower in recipients carrying ABCB1 3435CC genotype. For CYP3A5, recipients who received organs from CYP3A53/*3 donors had higher C/D ratios. But the donors' ABCB1 and recipients' CYP3A5 genotype did not affect the recipients' pharmacokinetics. Analysis of the combination of recipients' ABCB1 and donors' CYP3A5 genotypes revealed that the tacrolimus C/D ratios were significantly lower in the ABCB1 3435CC-carrying recipients, regardless of donors' CYP3A5 genotype. In conclusion, our finding suggests that the recipients' ABCB1 and donors' CYP3A5 genotype affect the tacrolimus dose requirements. ABCB1 C3435T polymorphism is a major determinant of tacrolimus trough concentration in Chinese liver transplant recipients, and recipients with 3435CC genotype will require higher dose of tacrolimus.
本研究旨在调查中国肝移植患者移植后第一个月他克莫司剂量需求的异质性是否与ABCB1和CYP3A5基因多态性相关。采用基于聚合酶链反应限制性位点多态性的方法，对50例中国肝移植受者及其相应供体（各50例）进行ABCB1和CYP3A5基因分型。使用IMx分析仪（雅培诊断实验室，伊利诺伊州雅培公园）上的免疫分析法测量他克莫司全血谷浓度。根据ABCB1和CYP3A5的等位基因状态，比较患者达到目标血药浓度所需的剂量以及剂量调整后的谷浓度（浓度/剂量[C/D]比值）。观察到23例受试者（23%）为ABCB1 3435CC，64例（64%）为3435CT，13例（13%）为3435TT。观察到13例受试者（13%）为CYP3A5*1/1，50例（50%）为1/3，37例（37%）为3/3。携带ABCB1 3435CC基因型的受者他克莫司C/D比值明显较低。对于CYP3A5，接受来自CYP3A53/*3供体器官的受者C/D比值较高。但供体的ABCB1和受者的CYP3A5基因型不影响受者的药代动力学。对受者ABCB1和供体CYP3A5基因型组合的分析显示，无论供体CYP3A5基因型如何，携带ABCB1 3435CC的受者他克莫司C/D比值均显著较低。总之，我们的研究结果表明，受者的ABCB1和供体的CYP3A5基因型影响他克莫司的剂量需求。ABCB1 C3435T多态性是中国肝移植受者他克莫司谷浓度的主要决定因素，3435CC基因型的受者需要更高剂量的他克莫司。
