CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients.
CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients.
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CYP3A5 和 ABCB1 基因型影响肾移植受者中他克莫司和西罗莫司的药代动力学
DOI：
10.1186/s40064-015-1425-5
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Li Y;Yan L;Shi Y;Bai Y;Tang J;Wang L
已有研究表明，细胞色素P450 3A5（CYP3A5）和ATP结合盒转运蛋白B1（ABCB1）基因多态性会影响他克莫司的血药浓度及用药剂量需求，但目前相关报告的结论并不一致。西罗莫司同样由CYP3A亚家族代谢，且是P-糖蛋白的底物。本研究旨在确定这些基因多态性是否会影响肾移植术后他克莫司（TAC）和西罗莫司（SRL）的谷浓度及用药剂量需求。本研究纳入153例肾移植受者，其中112例接受以他克莫司为基础的治疗方案，另外43例接受以西罗莫司为基础的治疗方案。受者平均随访时间为20个月（15 - 27个月）。所有肾移植受者均处于病情稳定阶段。记录每位受者他克莫司和西罗莫司的谷浓度及每日剂量。采用高分辨率熔解曲线分析（HRM分析）对所有受者的CYP3A5（6986A＞G）、CYP3A4内含子6（CYP3A4*22）、CYP3A4*18、ABCB1外显子26（3435C＞T）、外显子12（1236C＞T）以及2677G＞T/A单核苷酸多态性（SNP）进行基因分型。携带CYP3A5（*）3/（*）3基因型的受者，其他克莫司和西罗莫司的浓度/剂量比（C/D）显著高于携带（*）1等位基因的受者（P＜0.05）。然而，校正后的他克莫司和西罗莫司谷浓度或用药剂量需求与CYP3A4及ABCB1单核苷酸多态性之间无显著相关性。在接受以他克莫司或西罗莫司为基础治疗的受者中，CYP3A5基因（6986A＞G）可影响肾移植受者他克莫司和西罗莫司的药代动力学。
CYP3A5 and ABCB1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements, but the conclusion in the current reports were inconformity. Sirolimus are also metabolized by CYP3A subfamily and are substrates of the P-gp. The aim was to determine whether these polymorphisms affect tacrolimus (TAC) and sirolimus (SRL) trough concentrations and dose requirements after renal transplantation. 153 renal transplant recipients were enrolled into this study, 112 were treated with TAC-based regimen, Another 43 recipients received SRL-based regimen. The recipients’ mean follow-up time was 20 mo (range 15–27 mo). All renal transplant recipients were all in a stable stage. The trough concentration and daily dose of TAC and SRL were gained from each recipient. All recipients were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), CYP3A4*18, ABCB1 exon 26 (3435C>T), exon 12 (1236C>T) and 2677G>T/A SNPs by HRM analysis (high-resolution melting curve analysis). The TAC and SRL concentration/dose ratio (C/D) in recipients with CYP3A5 (*)3/(*)3 were significantly higher than that of those with (*)1 allele (P < 0.05). However, there was no significant correlation between adjusted TAC and SRL trough concentrations or dose requirements with CYP3A4 and ABCB1 SNPs genetic polymorphisms. In recipients with TAC-based or SRL-based therapy, the CYP3A5 genes (6986A>G) can influence the TAC and SRL pharmacokinetics in renal transplant recipients.