CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients
CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients
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DOI：
10.1097/ftd.0b013e31818a2a60
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发表时间：
2008-12-01
影响因子：
2.5
通讯作者：
Eap, Chin B.
中科院分区：
文献类型：
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作者：
Crettol, Severine;Venetz, Jean-Pierre;Eap, Chin B.
环孢素是细胞色素P450 (CYP) 3A和转运体ABCB1的底物，其多态性已被描述。特别是，CYP3A5 *3/*3基因型导致CYP3A5缺乏活性，而CYP3A7 *1/*1C基因型导致成人CYP3A7高表达。在73例肾（n = 64）或肺（n = 9）移植受者中，比较了经对数转化剂量调整的CYP3A和ABCB1基因型在移植后1、3、6和12个月的环孢素谷浓度和每体重日剂量。CYP3A5表达者（*1/*3基因型，n=8 ~ 10）在移植后1、3、6、12个月的环孢素谷浓度显著低于非表达者（*3/*3基因型，n= 55 ~ 59） （P < 0.01）。此外，移植后7天，CYP3A5表达者在环孢素浓度低于200 ng/mL目标浓度时出现的Uncorrected多于非表达者（优势比= 7.2；95%可信区间= 1.4 ~ 37.3;P = 0.009）。CYP3A4 rs4646437C>T影响环孢素动力学，T载体需要较高的环孢素剂量。CYP3A7*1C携带者在移植后第一年所需环孢素日剂量增加1.4 ~ 1.6倍（P < 0.05）。综上所述，CYP3A4、CYP3A5和CYP3A7多态性影响环孢素代谢，因此，它们的基因分型可能有助于与治疗药物监测相关联，以前瞻性地优化移植受体的环孢素处方。因此，应在随机对照临床试验中前瞻性地测试CYP3A基因型依赖性环孢素起始剂量，以评估其是否能改善移植后患者的预后，并具有充分的免疫抑制和毒性降低。
Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype, n=8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight(P < 0.01) than the nonexpressors (*3/*3 genotype, n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had Uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.