环孢素A的药物基因组学与个体化用药的研究现状及进展

摘要/Abstract

摘要： 环孢素(CsA)作为一种新型强效免疫抑制剂,近年来广泛应用于器官移植术后的抗排斥反应治疗。由于其治疗指数狭窄,个体间差异大,如何在临床合理使用CsA一直是广大学者关注的热点。CsA的生物利用度和代谢主要受药物代谢酶CYP3A和转运蛋白P-糖蛋白(P-gp)的影响,而不同个体间CYP3A与多药耐药基因(MDR1)基因多态性则是CYP3A酶和P-gp产生活性差异的分子机制。此外,合并用药、饮食结构等非遗传因素也是影响CsA疗效的重要原因,本文就近年来CsA药物基因组学研究进展结合非遗传因素予以综述,为临床个体化用药提供参考,确保患者安全合理用药。

关键词: 环孢素A, 基因多态性, 多药耐药基因, MDR1, 合并用药

Abstract: Cyclosporine (CsA), as a novel potent immunosuppressant, is widely used in organ transplantation in recent years. Due to its narrow therapeutic index and individual difference, it has been greatly concerned that how CsA can be used rationally in clinic. The bioavailability and metabolic of CsA are mainly affected by drug-metabolizing enzymes CYP3A and P-glycoprotein transporter protein (P-gp), while the individual differences of gene polymorphism of CYP3A and multi-drug resistance gene (MDR1) are the molecular mechanisms of the generation of activity difference. In addition, the combination therapy, diet and other non-genetic factors are also an important reason for the therapeutic effect of CsA. This paper reviews the pharmacogenomics research of CsA combined with non-genetic factors, in order to provide reference for clinical individualized medicine so as to ensure safety and rational use of drugs on patients.

Key words: cyclosporin A, gene polymorphism, CYP3A, MDR1, combination therapy

中图分类号:

R969.1

戴映, 张晶, 林美钦, 宋洪涛. 环孢素A的药物基因组学与个体化用药的研究现状及进展[J]. 中国临床药理学与治疗学, 2014, 19(8): 931-936.

DAI Ying, ZHANG Jing, LIN Mei-qing, SONG Hong-tao. Research current situation and progress on pharmacogenomics and personalized medicine of cyclosporine A[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(8): 931-936.

参考文献 36

[1]	Colombo D,AmmiratiE.Cyclosporine in transplantation - a history of converging timelines[J].J Biol Regul Homeost Agents,2011,25(4):493-504.
[2]	邵丽佳,徐瑞龙,朱以军.肾移植患者口服环孢素A的血药浓度监测分析[J]. 中国现代应用药学杂志,2007,24(3):247-248.
[3]	胡永芳,周宏灏.CYP3A4,CYP3A5和MDR1基因多态性对环孢素处置的影响[J].中国药理学通报,2005,21(3):257-261.
[4]	Min DI,Ellingrod VL.Association of the CYP3A4*1B 5'-flanking region polymorphism with cyclosporine pharmacokinetics in the healthy subjects[J].Ther Drug Monit,2003,25(3):305-309.
[5]	Zochowska D,Wyzgal J,Paczek L.Impact of CYP3A41B and CYP3A53 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients[J].Ann Transplant,2012,17(3):36-44.
[6]	刘亮,杨琳,张艳超,等.汉族人群药物代谢酶基因多态性位点基因型分布频率的研究[J]. 中华医学杂志,2009,89(38):2675-2681.
[7]	侯明明,侯颖,宋洪涛,等.肾移植患者CYP3A4基因多态性对他克莫司疗效和不良反应的影响[J].中国药房,2010,(26):2427-2429.
[8]	Qiu XY,Jiao Z,Zhang M,et al.Association of MDR1,CYP3A418B,and CYP3A53 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients[J].Eur J ClinPharmacol,2008,64(11):1069-1084.
[9]	Wang YY,Zhang M,Lu F,et al.CYP3A4 genetic polymorphisms predict cyclosporine-related clinical events in Chinese renal transplant recipients[J].Chin Med J (Engl), 2012,125(23):4233-4238.
[10]	Elens L,Bouamar R,Hesselink DA,et al.The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients[J].Pharmacogenet Genomics, 2012,22(5):373-380.
[11]	侯明明,宋洪涛,王庆华,等.肾移植患者CYP3A5*3基因多态性对他克莫司血药浓度/剂量比和疗效的影响[J].中国医院药学杂志,2010, 4:313-316.
[12]	Zhu HJ,Yuan SH,Fang Y,et al.The effect of CYP3A5 polymorphism ondose-adjusted cyclosporine concentrationin renal transplant recipients: a meta-analysis[J].Pharmacogenomics J,2011,11(3):237-246.
[13]	Tang HL,Ma LL,Xie HG,et al.Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients: a meta-analysis[J].Pharmacogenet Genomics,2010,20(9):525-531.
[14]	Finta C,Zaphiropoulos PG.The huma n cytochrome P450 3A locus. Gene evolution by capture of downstream exons[J].Gene,2000,260(1/2):13-23.
[15]	Jun KR,Lee W,Jang MS,et al.Tacrolimus concentrations in relation to CYP3A and ABCB1 polymorphisms among solid organ transplant recipients in Korea[J].Transplantation,2009,87(8):1225-1231.
[16]	任欣伟,杨卫红,李彦鹏,等.河南汉族人群CYP3A41G和CYP3AP13多态性及连锁不平衡分析[J].中国新药与临床杂志,2010, 8:602-605.
[17]	Zhu B,Chen GL,Chen XP,et al.Genotype of CYP3AP1 associated with CYP3A activity in Chinese Han population[J].Acta Pharmacol Sin,2002,23(6):567-572.
[18]	Eng HS,Mohamed Z,Calne R.The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograf t recipients[J].Kidney Int,2006,69(5):1858-1864.
[19]	丁征,邓婕,宋洪涛. MDR1基因多态性对相关药物药动学影响研究进展[J]. 中国临床药理学与治疗学,2011(10):1191-1196.
[20]	Ferraresso M,Belingheri M,Turolo S,et al.Long-term effects of ABCB1 and SXR SNPs on the systemic exposure to cyclosporine in pediatric kidney transplant patients[J].Pharmacogenomics,2013,14(13):1605-1613.
[21]	Wang Y,Wang C,Li J,et al.Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem[J].Eur J Clin Pharmacol,2009,65(3):239-247.
[22]	Zhang Y,Li JL,Fu Q,et al.Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients[J].Acta Pharmacol Sin,2013,34(4):555-560.
[23]	Foote CJ,Greer W,Kiberd B,et al.Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients[J].Transplantation,2007,83(10):1380-1384.
[24]	谢宇,宋洪涛,王庆华,等,CYP3A5*3和MDR1 G2677T/A基因多态性对肾移植患者环孢素A血药浓度及疗效的影响[J]. 中国药学杂志,2011(20):1591-1596.
[25]	李海菊,平卫伟,宋丽华,等. 多药耐药基因1 C3435T 基因多态性对环孢素A药物动力学影响的Meta分析[J].中国组织工程研究,2012,16(53):10037-10042.
[26]	Garcia M,Macias RM,Cubero JJ,et al.ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients[J].Eur J ClinPharmacol,2013,69(3):385-393.
[27]	何晓静,菅凌燕.ABCB1基因多态性在中国骨髓移植患者服用环孢素A所致肝损伤的研究[J].中国临床药理学杂志,2013, 8:575-577.
[28]	Llaudo I,Colom H,Gimenez-Bonafe P,et al.Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study[J].Transpl Int, 2013,26(2):177-186.
[29]	Jordán DLC,Herrero CMJ,Sánchez LI,et al.Pharmacogenetic study of ABCB1 and CYP3A5 genes during the first year following heart transplantation regarding tacrolimus or cyclosporine levels[J].Transplant Proc,2011,43(6):2241-2243.
[30]	Zhang JJ,Zhang H,Ding XL,et al.Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers[J].Eur J Clin Pharmacol,2013,69(4):807-812.
[31]	Elens L,Hesselink DA,Bouamar R,et al.Impact of POR*28 on the Pharmacokinetics of Tacrolimus and Cyclosporine a in Renal Transplant Patients[J].Ther Drug Monit,2014, 36(1): 71-79.
[32]	Qiu XY,Jiao Z,Zhang M,et al.Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients[J].Nephrology (Carlton),2012,17(4):423-430.
[33]	Zhou H,Gao Y,Cheng XL,et al.Population pharmacokinetics of cyclosporine A based on NONMEM in Chinese allogeneic hematopoietic stem cell transplantation recipients[J].Eur J Drug Metab Pharmacokinet,2012,37(4):271-278.
[34]	Yang SY,Tsai SY,Hou YC,et al.Inductive modulation on P-glycoprotein and cytochrome 3A by resveratrol, a constituent of grapes[J].Food Chem,2012,133(3):683-688.
[35]	Yu CP,Wu PP, Hou YC,et al.Quercetin and rutin reduced the bioavailability of cyclosporine from Neoral,an immunosuppressant,through activating P-glycoprotein and CYP3A4[J].J Agric Food Chem,2011,59(9):4644-4648.
[36]	Ryan C,Amor KT,Menter A.The use of cyclosporine in dermatology:part II[J].J Am Acad Dermatol,2010,63(6):949-972,973-974.