Peking University Third Hospital, Peking University Therapeutic Drug Monitoring and Clinical Toxicology Center, Beijing, China.
Pharmacogenet Genomics. 2011 Nov;21(11):713-20. doi: 10.1097/FPC.0b013e32834a48ca.
CYP3A5 genetic polymorphisms contribute to marked interindividual differences in the metabolism of and response to tacrolimus in humans.
This study was aimed to clarify the impact of the CYP3A5*3 variant on tacrolimus dose requirements and acute rejection rates in patients with organ transplantation.
A literature search was performed up to August 2009 by using the Cochrane library, PubMed, Medline, and EMBase.
Twenty-three studies (a total of 1779 patients) were included in this meta-analysis. Eighteen studies (1443 patients) were involved in renal transplantation and five studies (336 patients) in liver transplantation. Results of meta-analysis demonstrated that, in renal transplant patients, despite the presence of significant heterogeneity, CYP3A5 expressers required higher mean tacrolimus daily doses by 0.045 mg/kg (95% confidence interval (CI), 0.033-0.056) than nonexpressers. Furthermore, sub-analysis of the time of posttransplantation showed that CYP3A5 expressers required higher daily doses than nonexpressers by 0.010, 0.084, 0.041, 0.037, and 0.044 mg/kg at week 2, and at month 1, 3, 6, and 12, respectively. Subset analysis of the ethnicity of organ recipients indicated that mean tacrolimus daily doses were 0.056, 0.037, and 0.077 mg/kg higher in CYP3A5 expressers than non- expressers for white, Chinese, and Japanese patients, respectively. In contrast, for liver transplant patients, higher tacrolimus daily doses were required not only in CYP3A5 expressers of the organ donors than nonexpressers by 0.024 mg/kg (95% CI, 0.019-0.028), but also in CYP3A5 expresser of the organ recipients than nonexpresser by 0.012 mg/kg (95% CI, 0.005-0.018). However, a significant difference in the acute organ rejection rate was observed only at one month (odds ratio, 3.27; 95% CI, 1.57-6.81; P=0.002).
Tacrolimus daily dose requirements may vary with the presence of the CYP3A5*3 variant, ethnicity of the organ recipients, and the time of posttransplantation. In addition, the acute organ rejection rate may be higher in CYP3A5 expressers than nonexpressers over the first month after transplantation.
CYP3A5 基因多态性导致人体中美他环素代谢和反应存在显著的个体间差异。
本研究旨在阐明 CYP3A5*3 变异对器官移植患者中环孢菌素剂量需求和急性排斥反应率的影响。
截至 2009 年 8 月，通过 Cochrane 图书馆、PubMed、Medline 和 EMBase 进行了文献检索。
本荟萃分析纳入了 23 项研究（共 1779 名患者）。18 项研究（1443 名患者）涉及肾移植，5 项研究（336 名患者）涉及肝移植。荟萃分析结果表明，尽管存在显著的异质性，但在肾移植患者中，CYP3A5 表达者每天需要多使用 0.045mg/kg 的他克莫司（95%置信区间（CI）：0.033-0.056）。此外，移植后时间的亚分析表明，CYP3A5 表达者每天需要比非表达者多使用 0.010、0.084、0.041、0.037 和 0.044mg/kg，分别在第 2 周和第 1、3、6 和 12 个月。受体器官受者种族的亚组分析表明，白种人、中国人和日本人的 CYP3A5 表达者每天需要多使用 0.056、0.037 和 0.077mg/kg 的他克莫司。相比之下，对于肝移植患者，器官供者的 CYP3A5 表达者不仅每天需要比非表达者多使用 0.024mg/kg（95%CI：0.019-0.028），而且受体的 CYP3A5 表达者每天也需要比非表达者多使用 0.012mg/kg（95%CI：0.005-0.018）。然而，仅在一个月时观察到器官急性排斥率的显著差异（比值比，3.27；95%CI：1.57-6.81；P=0.002）。
他克莫司的日剂量需求可能因 CYP3A5*3 变异、受体器官受者的种族以及移植后的时间而有所不同。此外，在移植后第一个月，CYP3A5 表达者的器官急性排斥率可能高于非表达者。
