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| CYP3A5和ABCB1多态性对肾移植受者由环孢素转换为他克莫司个体化给药的影响 |
| 王学彬1,王卓1*,高申1,章玥1,高丽红1,尹东锋2,曹爱霖1,田泾1,张文静1,钱皎1,肖成武3,杨庆3* |
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(1. 第二军医大学长海医院药学部, 上海 200433;
2. 兰州军区乌鲁木齐总医院药剂科, 乌鲁木齐 830000;
3. 第二军医大学长海医院泌尿外科, 上海 200433
*通信作者) |
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| 摘要: |
| 目的 探讨CYP3A5和ABCB1基因多态性对肾移植受者将环孢素(cyclosporine A, CsA)转换为他克莫司(tacrolimus, FK506)后的初始他克莫司个体化给药的影响。方法 利用聚合酶链反应(PCR)和限制性内切片段长度多态性(PCR-RFLP)方法检测CYP3A5*3(A6989G)和ABCB1 3个位点exon12 C1236T、exon21 G(A)2677T和exon26 C3435T基因型;回顾性评价CYP3A5和ABCB1 3个位点基因型及单倍体型对由CsA转换为他克莫司的肾移植受者他克莫司初始血药谷浓度/剂量比(concentration/dose, C0/D)的影响。结果 对于由CsA转换为他克莫司的肾移植受者, 在转换后的第7、14、21和28天, CYP3A5 AA、AG与GG组的他克莫司C0/D之间差异有统计学意义(P<0.05);当第28天CYP3A5 AA组和AG组的他克莫司日剂量D分别达到GG组的3.5倍[(0.14±0.03) mg·kg-1 vs (0.04±0.01) mg·kg-1, P=0.00]和1.75倍[(0.07±0.03) mg·kg-1 vs (0.04±0.01) mg·kg-1, P=0.00]时, CYP3A5不同基因型的他克莫司C0才达到同一靶浓度。对于由CsA转换为他克莫司的CYP3A5GG肾移植受者, ABCB1C1236T、G(A)2677T和C3435T基因型及其纯合子单倍体型对初始他克莫司C0/D无影响(P>0.05)。结论 对于需将CsA转换为他克莫司肾移植受者, 应根据CYP3A5基因型选择他克莫司的初始给药日剂量, 以期迅速达到有效免疫抑制效果。 |
| 关键词: 细胞色素P450 CYP3A5 P糖蛋白 环孢素 他克莫司 单核苷酸多态性 肾移植 |
| DOI：10.3724/SP.J.1008.2014.01320 |
| 投稿时间：2014-04-11修订日期：2014-06-30 |
| 基金项目:国家科技部重大新药创制专项课题(2012ZX09303-011-002), 第二军医大学长海医院“1255”基金学科特色提升项目(CH125520400). |
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| Impact of CYP3A5 and ABCB1 polymorphisms on drug switching from cyclosporine to tacrolimus for individualized treatment of renal transplant recipients |
| WANG Xue-bin1,WANG Zhuo1*,GAO Shen1,ZHANG Yue1,GAO Li-hong1,YIN Dong-feng2,CAO Ai-lin1,TIAN Jing1,ZHANG Wen-jing1,QIAN Jiao1,XIAO Cheng-wu3,YANG Qing3* |
(1. Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200433, China;
2. Department of Pharmacy, Urumqi General Hospital, PLA Lanzhou Military Area Command, Urumqi 830000, Xinjiang, China;
3. Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
*Corresponding authors) |
| Abstract: |
| Objective To investigate the impact of CYP3A5 and ABCB1 polymorphisms on the initial individualized treatment with tacrolimus (FK506) in renal transplant recipients during switching from cyclosporine (CsA) to FK506. Methods Polymerase chain reaction and restriction fragment length polymorphism method (PCR-RFLP) was employed to investigate CYP3A5 (A6989G) and ABCB1 (exon12[C1236T],exon21G[A]2677T and exon26[C3435T]) genotype data. The initial trough concentration/dose (C0/D) values were compared among different CYP3A5 genotypes in renal transplant recipients switching from CsA to FK506 using one-way ANOVA. In addition, the initial C0/D values were also compared among different ABCB1 (exon12[C1236T],exon21G[A]2677T and exon26[C3435T]) genotypes and their haplotypes using one-way ANOVA. Results The FK506 C0/D values were significantly different between different CYP3A5 genotypes (AA, AG and GG) at the 7th, 14th, 21th and 28th day of conversion from CsA to FK506 in renal transplant recipients (P<0.05). Only on the 28th day of conversion, when the FK506 D in CYP3A5AA group was 3.5-fold that of CYP3A5GG group([0.14±0.03] mg·kg-1·d-1 vs [0.04±0.01] mg·kg-1·d-1, P=0.00) and the FK506 D in CYP3A5AG group was 1.75-fold that of CYP3A5GG group([0.07±0.03] mg·kg-1·d-1 vs [0.04±0.01] mg·kg-1·d-1, P=0.00), the FK506 C0 in different CYP3A5 genotypes reached the same target concentration. The initial FK506 C0/D was not associated with different ABCB1 (exon12 [C1236T], exon21 G[A]2677T and exon26 [C3435T]) genotypes or their haplotypes in renal transplant recipients. Conclusion Appropriate initial daily dose of FK506 should be selected according to CYP3A5 genotype in order to quickly achieve the target immunosuppression in renal transplant recipients who are switching immunosuppressive regimen from CsA to FK506. |
| Key words: cytochrome P-450 CYP3A5 P-glycoprotein cyclosporine tacrolimus single nucleotide polymorphism kidney transplantation |
