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CYP3A4、CYP3A5和CYP3A7的基因多态性对中国汉族肾移植患者他克莫司药动学的影响

Influence of CYP3A4, CYP3A5 and CYP3A7 Polymorphisms on Tacrolimus Pharmacokinetics in Chinese Renal Transplant Patients

DOI：

中文关键词: 他克莫司 CYP3A5 CYP3A7 P 糖蛋白单核苷酸多态性肾移植

英文关键词:Tacrolimus CYP3A5 CYP3A7 P glycoprotein Polymorphisms Renal transplantation

基金项目:国家自然科学基金青年科学基金项目（编号：81302854），上海市自然科学基金面上项目（编号：13ZR1405200），上海市“医苑新星”青年医学人才培养资助计划项目（编号：沪卫计药政[2018]1号）

作者	单位
邱晓燕1 武卓1 徐璐扬1 张明2 钟明康1	复旦大学附属华山医院 1. 临床药学室；2. 肾病科上海 200040

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中文摘要:

摘要目的：探讨中国汉族肾移植患者中，CYP3A5*3（rs776746）、CYP3A4*1G(rs2242480)、CYP3A4 rs4646437、CYP3A7 rs2257401及CYP3A7 rs10211单核苷酸多态性对免疫抑制药他克莫司（TAC）药动学的影响。方法：采用直接测序法，对85例肾移植的患者进行基因分型。采用酶放大免疫分析法测定患者TAC的谷浓度（C0）。比较不同基因型患者间TAC浓度剂量比值的差异。结果：在85例肾移植患者中，CYP3A5*3 A、CYP3A4*1G T、CYP3A4 rs4646437 T、CYP3A7 rs2257401C及CYP3A7 rs10211 G等位基因的频率分别为29.4%,27.6%,13.5%,26.5%及27.6%。肾移植术后1个月时，CYP3A5*3、CYP3A7 rs2257401及CYP3A7 rs10211影响TAC的谷浓度（P<0.01）。CYP3A5*3 A、CYP3A7 rs2257401 C及CYP3A7 rs10211 G等位基因携带者，TAC剂量校正浓度分别比其相应非携带者剂量校正浓度低约50%左右。而本研究未发现CYP3A4*1G和CYP3A4 rs4646437基因多态性与TAC校正谷浓度相关（P>0.05）。结论：在中国汉族肾移植患者中，CYP3A5*3、CYP3A7 rs2257401及CYP3A7 rs10211的单核苷酸多态性与移植术后1个月内TAC的药代动力学有相关性，但把这种相关性应用在临床上，以优化他克莫司的剂量，尚待进一步的研究。

英文摘要:

ABSTRACT Objective:The purpose of this study was to investigate the potential impact of single nucleotide polymorphisms like CYP3A5*3（rs776746），CYP3A4*1G(rs2242480), CYP3A4 rs4646437, CYP3A7 rs2257401 and CYP3A7 rs10211 on the pharmacokinetics of tacrolimus in Chinese renal transplant patients. Methods: Using direct sequencing, genotypes was detected in 85 renal transplant patients. The concentrations (C0) of tacrolimus was measured with enzyme amplification immunoassay. The TAC concentration dosage ratio of different genotypes were compared. Results: In 85 renal transplantation patients, the frequency of CYP3A5*3 A, CYP3A4*1G T, CYP3A4 rs4646437 T, CYP3A7 rs2257401C and CYP3A7 rs10211G allele were 29.4%, 27.6%, 13.5%, 26.5% and 27.6%. One month after kidney transplantation, the TAC C0 were influenced by CYP3A5*3, CYP3A7 rs2257401 and CYP3A7 rs10211 (P<0.01). In patients with CYP3A5*3 A, CYP3A7 rs2257401 and CYP3A7 rs10211 G allele, the TAC C0 were about 50% lower than those non carriers. In addition, there were no significant differences in tacrolimus concentration between CYP3A7 rs10211 G and CYP3A4 rs4646437 allele (P>0.05). Conclusion: In Chinese renal transplant patients, it had the correlation between single nucleotide polymorphisms of CYP3A5*3, CYP3A7 rs2257401 and CYP3A7 rs10211 and pharmacokinetics of TAC within 1 month post transplant surgery. But it needed further research to put it into use clinically as to optimize tacrolimus dosage.

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