Lee Jun, Wang Rongrong, Yang Yuan, Lu Xiaoyang, Zhang Xingguo, Wang Linrun, Lou Yan
Department of Clinical Pharmacology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Clinical Pharmacology, Zhuji City Sixth People's Hospital, Zhuji, China.
Basic Clin Pharmacol Toxicol. 2015 Aug;117(2):117-25. doi: 10.1111/bcpt.12371. Epub 2015 Jan 21.
Cyclosporine A (CsA) is a substrate of the multi-drug efflux pump P-glycoprotein (P-gp) encoded by ABCB1. Among the various single nucleotide polymorphisms (SNPs) of ABCB1, C3435T has been extensively investigated to determine the relationship with the pharmacokinetics of CsA. However, the results are controversial. This meta-analysis was designed to evaluate the influence of C3435T SNP on the dose-adjusted trough (C0 /D) and peak (Cmax /D) concentrations of CsA. Based on a literature search of four authoritative databases, 13 studies since 2001 concerning 1293 kidney transplant recipients were included. The results indicated a significant difference of C0 /D and Cmax /D between 3435CC and 3435TT genotype carriers (weighted mean difference (WMD) of C0 /D: 4.18 (ng ml(-1))/(mg kg(-1)), 95% CIs: 1.00-7.37, p = 0.01; WMD of Cmax /D: 20.85 (ng ml(-1))/(mg kg(-1)), 95% CIs: 2.25-39.46, p = 0.03). Subgroup analysis by ethnicity demonstrated that C0 /D was lower in Asian CC versus TT genotype carriers (WMD = 10.32 (ng ml(-1))/(mg kg(-1)), 95% CIs: 4.78-15.85, p = 0.0003) but did not vary by genotype for Caucasian recipients. Moreover, significant variation of C0 /D was found at 1 week and 1-3 months after transplantation between CC and TT genotype carriers. Therefore, this meta-analysis showed a correlation between ABCB1 C3435T polymorphism and the dose-adjusted concentration of CsA. Patients with 3435CC genotype will require a higher dose of CsA to achieve target therapeutic concentrations when compared with 3435TT carriers after kidney transplantation, especially in the Asian population and especially during the early and middle time periods after transplantation.
环孢素A（CsA）是由ABCB1编码的多药外排泵P-糖蛋白（P-gp）的底物。在ABCB1的各种单核苷酸多态性（SNP）中，C3435T已被广泛研究以确定其与CsA药代动力学的关系。然而，结果存在争议。本荟萃分析旨在评估C3435T SNP对CsA剂量调整后的谷浓度（C0 /D）和峰浓度（Cmax /D）的影响。基于对四个权威数据库的文献检索，纳入了自2001年以来关于1293例肾移植受者的13项研究。结果表明，3435CC和3435TT基因型携带者之间的C0 /D和Cmax /D存在显著差异（C0 /D的加权平均差（WMD）：4.18（ng ml(-1)）/（mg kg(-1)），95%置信区间：1.00 - 7.37，p = 0.01；Cmax /D的WMD：20.85（ng ml(-1)）/（mg kg(-1)），95%置信区间：2.25 - 39.46，p = 0.03）。按种族进行的亚组分析表明，亚洲CC基因型携带者与TT基因型携带者相比，C0 /D较低（WMD = 10.32（ng ml(-1)）/（mg kg(-1)），95%置信区间：4.78 - 15.85，p = 0.0003），但白种人受者的C0 /D不因基因型而有所不同。此外，在移植后1周和1 - 3个月时，CC和TT基因型携带者之间的C0 /D存在显著差异。因此，本荟萃分析表明ABCB1 C3435T多态性与CsA的剂量调整浓度之间存在相关性。肾移植后，与3435TT携带者相比，3435CC基因型患者需要更高剂量的CsA才能达到目标治疗浓度，尤其是在亚洲人群中，特别是在移植后的早期和中期。
