Genvigir Fabiana D V, Nishikawa Alvaro M, Felipe Claudia R, Tedesco-Silva Helio, Oliveira Nagilla, Salazar Antony B C, Medina-Pestana Jose O, Doi Sonia Q, Hirata Mario H, Hirata Rosario D C
Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil.
Pharmacotherapy. 2017 May;37(5):535-545. doi: 10.1002/phar.1928. Epub 2017 May 9.
To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients.
Pharmacogenetic analysis of patients enrolled in a previously published study.
One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation.
ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C83, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A53C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C83 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A53C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05).
The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.
探讨编码代谢酶（CYP2C8、CYP2J2和UGT2B7）及转运蛋白（ABCC2和ABCG2）的基因中的单核苷酸多态性（SNP）对巴西肾移植受者中他克莫司和麦考酚钠的剂量、剂量调整后的谷血浓度（C:D比值）、临床结局及不良事件发生情况的影响。
对一项既往发表研究中纳入的患者进行药物遗传学分析。
148例成年肾移植受者，在移植后90天接受他克莫司、肠溶型麦考酚钠和泼尼松治疗。
通过实时聚合酶链反应测定ABCC2基因的c.-24C>T和c.3972C>T、ABCG2基因的c.421C>A、CYP2C83、CYP2J2基因的c.-76G>T以及UGT2B7基因的c.372A>G单核苷酸多态性。使用CYP3A53C单核苷酸多态性数据消除该变异对结果的混杂影响。ABCC2基因c.3972T等位基因携带者的他克莫司C:D值高于c.3972CC基因型携带者。CYP2C83变异也与稍高的他克莫司C:D值及较高的估计肾小球滤过率相关，但仅在不表达CYP3A5的患者（CYP3A53C/*3C携带者）中如此。没有任何单核苷酸多态性与麦考酚钠剂量或活检证实的急性排斥反应发作或移植肾功能延迟相关。CYP2J2基因的c.-76T等位基因与治疗引起的恶心和/或呕吐风险增加相关（比值比：5.30，95%置信区间1.49 - 18.79，p<0.05）。
ABCC2基因的c.3972C>T多态性影响巴西肾移植受者的他克莫司C:D比值。此外，CYP2C8*3和CYP2J2基因的c.-76G>T单核苷酸多态性影响这些患者的肾功能以及他克莫司和麦考酚钠治疗期间不良事件的发生情况。
