自身免疫性疾病患者CYP3A4、CYP2C8和CYP3A5基因多态性与羟氯喹不良反应/血药浓度的相关性研究
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摘要
目的:研究自身免疫性疾病(AID)患者细胞色素P_(450)(CYP)酶的亚型CYP3A4、CYP2C8和CYP3A5的基因多态性与羟氯喹不良反应、血药浓度的相关性,为羟氯喹的临床个体化用药提供参考。方法:病例来自安徽医科大学第一附属医院风湿免疫科2017年7月-2018年8月收治的因长期(>6个月)服用羟氯喹(日剂量为200～400 mg)出现不良反应的77例AID患者,收集患者信息、血样和不良反应发生情况,按不良反应发生部位分为肝功能正常组和肝功能异常组、肾功能正常组和肾功能异常组、眼部正常组和眼部异常组,采用高效液相色谱法测定羟氯喹全血药物浓度,MassARRAY系统检测患者CYP3A4、CYP2C8和CYP3A5的基因型,通过χ~2检验分析不同基因型患者羟氯喹不良反应的发生差异,通过两独立样本t检验和单因素方差分析不同基因型患者羟氯喹血药浓度的差异。结果:CYP3A5 rs4646453位点在肾功能正常组与肾功能异常组的分布差异具有统计学意义(P<0.05),肾功能异常组患者中CC基因型较AA+AC基因型的发生率高;CYP2C8 rs10882526位点在肝功能正常组与肝功能异常组的分布差异具有统计学意义(P<0.05),肝功能异常组患者中等位基因G较等位基因A的发生率高,AG基因型较AA基因型的发生率高。77例AID患者CYP3A4、CYP2C8和CYP3A5的基因多态性与血药浓度无显著相关性。在亚组分析时,58例系统性红斑狼疮(SLE)患者中CYP2C8 rs10882521的GT、GG和TT基因型的平均血药浓度分别为514.1、735.3、785.9 ng/mL,其中GG和TT基因型明显高于GT基因型(P<0.05)。结论:AID患者携带CYP3A5 rs4646453 CC基因型服用羟氯喹肾功能异常的发生率更高,携带CYP2C8 rs10882526位点的等位基因G和AG基因型服用羟氯喹肝功能异常的发生率更高。SLE患者服用相同剂量羟氯喹,携带CYP2C8 rs10882521 GT基因型较其他基因型患者血药浓度低。
OBJECTIVE:To study the relationship of CYP3A4,CYP2C8 and CYP3A5 gene polymorphism with ADR/blood concentration of hydroxychloroquine in patients with autoimmune disease(AID), and to provide reference for individual medication of hydroxychloroquine. METHODS:Totally 77 AID patients,who were treated with hydroxychloroquine(daily dose of200 mg to 400 mg)for a long-term(>6 months),were selected from the department of rheumatology and immunology,the First Affiliated Hospital of Anhui Medical University during Jul. 2017 to Aug. 2018. The information,blood sample and ADR of them were collected. Those patients were divided into normal liver function group,abnormal liver function group,normal renal function group,abnormal renal function group,normal eye group and abnormal eye group according to the site of ADR. The concentration of hydroxychloroquine was determined by HPLC. Genotype of CYP3A4,CYP2C8 and CYP3A5 were detected by MassARRAY microarray system. The differences of hydroxychloroquine-induced ADR in different genotypes were analyzed by χ~2 test. The blood concentration difference of hydroxychloroquine in different genotypes were analyzed by independent sample t-test and one-way ANOVA. RESULTS:There was statistical significance in the distribution of CYP3A5 rs4646453 locus between normal renal function group and abnormal renal function group(P<0.05). The incidence of CC genotype was higher than that of AA + AC genotype in abnormal renal function group. There was statistical significance in the distribution of CYP2C8 rs10882526 locus between normal liver function group and abnormal liver function group(P<0.05). The incidence of allele G was higher than that of allele A in abnormal liver function group,and the incidence of AG genotype was higherthan that of AA genotype. There was no significant correlation of the gene polymorphisms of CYP3A4,CYP2C8 and CYP3A5 with blood concentration among 77 AID patients. In subgroup analysis,blood concentration of GT,GG and TT genotypes of CYP2C8 rs10882521 in 58 patients with systemic lupus erythematosus(SLE)were 514.1,735.3 and 785.9 ng/mL,respectively;GG and TT genotypes were significantly higher than GT genotype(P<0.05). CONCLUSIONS:AID patients with CYP3A5 rs4646453 CC genotype have a higher incidence of renal dysfunction due to taking hydroxychloroquine;patients with CYP2C8 rs10882526 locus allele G and AG have a relatively high incidence of renal dysfunction due to taking hydroxychloroquine. When SLE patients taking the same dose of hydroxychloroquine,the blood concentration of hydroxychloroquine in patients carrying CYP2C8 rs10882521 GT genotype is lower than other genotypes.
OBJECTIVE:To study the relationship of CYP3A4,CYP2C8 and CYP3A5 gene polymorphism with ADR/blood concentration of hydroxychloroquine in patients with autoimmune disease(AID), and to provide reference for individual medication of hydroxychloroquine. METHODS:Totally 77 AID patients,who were treated with hydroxychloroquine(daily dose of200 mg to 400 mg)for a long-term(>6 months),were selected from the department of rheumatology and immunology,the First Affiliated Hospital of Anhui Medical University during Jul. 2017 to Aug. 2018. The information,blood sample and ADR of them were collected. Those patients were divided into normal liver function group,abnormal liver function group,normal renal function group,abnormal renal function group,normal eye group and abnormal eye group according to the site of ADR. The concentration of hydroxychloroquine was determined by HPLC. Genotype of CYP3A4,CYP2C8 and CYP3A5 were detected by MassARRAY microarray system. The differences of hydroxychloroquine-induced ADR in different genotypes were analyzed by χ~2 test. The blood concentration difference of hydroxychloroquine in different genotypes were analyzed by independent sample t-test and one-way ANOVA. RESULTS:There was statistical significance in the distribution of CYP3A5 rs4646453 locus between normal renal function group and abnormal renal function group(P<0.05). The incidence of CC genotype was higher than that of AA + AC genotype in abnormal renal function group. There was statistical significance in the distribution of CYP2C8 rs10882526 locus between normal liver function group and abnormal liver function group(P<0.05). The incidence of allele G was higher than that of allele A in abnormal liver function group,and the incidence of AG genotype was higherthan that of AA genotype. There was no significant correlation of the gene polymorphisms of CYP3A4,CYP2C8 and CYP3A5 with blood concentration among 77 AID patients. In subgroup analysis,blood concentration of GT,GG and TT genotypes of CYP2C8 rs10882521 in 58 patients with systemic lupus erythematosus(SLE)were 514.1,735.3 and 785.9 ng/mL,respectively;GG and TT genotypes were significantly higher than GT genotype(P<0.05). CONCLUSIONS:AID patients with CYP3A5 rs4646453 CC genotype have a higher incidence of renal dysfunction due to taking hydroxychloroquine;patients with CYP2C8 rs10882526 locus allele G and AG have a relatively high incidence of renal dysfunction due to taking hydroxychloroquine. When SLE patients taking the same dose of hydroxychloroquine,the blood concentration of hydroxychloroquine in patients carrying CYP2C8 rs10882521 GT genotype is lower than other genotypes.
引文
[1]陈新谦,金有豫,汤光.新编药物学[M].17版.北京:人民卫生出版社,2011:137-138.
[2]闫琳毅,张海艇,林玮,等.自身免疫性疾病患者长期使用羟氯喹治疗的安全性[J].中华临床免疫和变态反应杂志,2015,9(4):262-266.
[3]JALLOULI M,GALICIER L,ZAHR N,et al.Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus[J].Arthritis Rheumatol,2015,67(8):2176-2184.
[4]AL-RAWI H,MEGGITT SJ,WILLIAMS FM,et al.Steadystate pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus[J].Lupus,2018,27(5):847-852.
[5]LEE JY,VINAYAGAMOORTHY N,HAN K,et al.Association of polymorphisms of cytochrome P4502D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus[J].Arthritis Rheumato,2016,68(1):184-190.
[6]中华医学会风湿病学分会.2018中国类风湿关节炎诊疗指南[J].中华内科杂志,2018,57(4):242-251.
[7]中华医学会风湿免疫分会.系统性红斑狼疮诊断及治疗指南[J].中华风湿病学杂志,2010,14(5):342-346.
[8]刘婷婷,余威,杨春兰,等.羟氯喹治疗自身免疫性疾病血药浓度影响因素分析[J].中国临床药理学与治疗学,2018,23(12):1359-1363.
[9]YEON LEE J,LEE J,KI KWOK S,et al.Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus[J].Arthritis Care Res(Hoboken),2017,69(4):536-542.
[10]DURCAN L,CLARKE WA,MAGDER LS,et al.Hydroxychloroquine blood levels in systemic lupus erythematosus:clarifying dosing controversies and improving adherence[J].Rheumato,2015,42(11):2092-2097.
[11]MELLES RB,MARMOR MF.The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[J].JAMA Ophthalmol,2014,132(12):1453-1460.
[12]CHIANG E,JAMPOL LM,FAWZI AA.Retinal toxicity found in a patient with systemic lupus erythematosus prior to 5 years of treatment with hydroxychloroquine[J].Rheumatology(Oxford),2014,53(11):2001.
[13]O’LAUGHLIN JP,MEHTA PH,WONG BC.Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine[J].Case Rep in Cardiol,2016.DOI:10.1155/2016/4626279.
[14]CUNHA C,ALEXANDER S,ASHBY D,et al.Hydroxycloroquine blood concentration in lupus nephritis:a determinant of disease out-come?[J].Nephrol Dial Transplant,2018,33(9):1604-1610.
[15]COSTEDOAT-CHALUMESU N,AMOURA Z,HULOTJS,et al.Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus[J].Ann Rheum Dis,2007,66(6):821-824.
[16]罗雪梅,姚瑶,葛卫红.细胞色素P4503A4*1G与腺苷三磷酸结合转运蛋白G超家族成员2基因多态性对羟氯喹血药浓度的影响[J].中国临床药理学杂志,2017,33(24):2572-2574.
[17]KIM KA,PARK JY,LEE JS,et al.Cytochrome P4502C8and CYP3A4/5 are involved in chloroquine metabolish in human liver microsomes[J].Arch Pharm Res,2003,26(8):631-637.
[18]周鹏,张璇,杨叶雅.汉族患者CYP3A4*18基因多态性与阿立哌唑血药浓度及不良反应的相关性研究[J].中国药房,2014,25(28):2618-2620.
[2]闫琳毅,张海艇,林玮,等.自身免疫性疾病患者长期使用羟氯喹治疗的安全性[J].中华临床免疫和变态反应杂志,2015,9(4):262-266.
[3]JALLOULI M,GALICIER L,ZAHR N,et al.Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus[J].Arthritis Rheumatol,2015,67(8):2176-2184.
[4]AL-RAWI H,MEGGITT SJ,WILLIAMS FM,et al.Steadystate pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus[J].Lupus,2018,27(5):847-852.
[5]LEE JY,VINAYAGAMOORTHY N,HAN K,et al.Association of polymorphisms of cytochrome P4502D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus[J].Arthritis Rheumato,2016,68(1):184-190.
[6]中华医学会风湿病学分会.2018中国类风湿关节炎诊疗指南[J].中华内科杂志,2018,57(4):242-251.
[7]中华医学会风湿免疫分会.系统性红斑狼疮诊断及治疗指南[J].中华风湿病学杂志,2010,14(5):342-346.
[8]刘婷婷,余威,杨春兰,等.羟氯喹治疗自身免疫性疾病血药浓度影响因素分析[J].中国临床药理学与治疗学,2018,23(12):1359-1363.
[9]YEON LEE J,LEE J,KI KWOK S,et al.Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus[J].Arthritis Care Res(Hoboken),2017,69(4):536-542.
[10]DURCAN L,CLARKE WA,MAGDER LS,et al.Hydroxychloroquine blood levels in systemic lupus erythematosus:clarifying dosing controversies and improving adherence[J].Rheumato,2015,42(11):2092-2097.
[11]MELLES RB,MARMOR MF.The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[J].JAMA Ophthalmol,2014,132(12):1453-1460.
[12]CHIANG E,JAMPOL LM,FAWZI AA.Retinal toxicity found in a patient with systemic lupus erythematosus prior to 5 years of treatment with hydroxychloroquine[J].Rheumatology(Oxford),2014,53(11):2001.
[13]O’LAUGHLIN JP,MEHTA PH,WONG BC.Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine[J].Case Rep in Cardiol,2016.DOI:10.1155/2016/4626279.
[14]CUNHA C,ALEXANDER S,ASHBY D,et al.Hydroxycloroquine blood concentration in lupus nephritis:a determinant of disease out-come?[J].Nephrol Dial Transplant,2018,33(9):1604-1610.
[15]COSTEDOAT-CHALUMESU N,AMOURA Z,HULOTJS,et al.Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus[J].Ann Rheum Dis,2007,66(6):821-824.
[16]罗雪梅,姚瑶,葛卫红.细胞色素P4503A4*1G与腺苷三磷酸结合转运蛋白G超家族成员2基因多态性对羟氯喹血药浓度的影响[J].中国临床药理学杂志,2017,33(24):2572-2574.
[17]KIM KA,PARK JY,LEE JS,et al.Cytochrome P4502C8and CYP3A4/5 are involved in chloroquine metabolish in human liver microsomes[J].Arch Pharm Res,2003,26(8):631-637.
[18]周鹏,张璇,杨叶雅.汉族患者CYP3A4*18基因多态性与阿立哌唑血药浓度及不良反应的相关性研究[J].中国药房,2014,25(28):2618-2620.