系统性红斑狼疮患者中基因多态性对羟氯喹血药浓度的影响
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摘要
目的评估系统性红斑狼疮(SLE)患者体内细胞色素P450(CYP) 3A5,CYP3A4,CYP2D6基因多态性对羟氯喹(HCQ)血药浓度的影响。方法收集130例服用羟氯喹大于1年以上的SLE患者,用高效液相色谱法对其体内羟氯喹浓度进行测定,通过Sanger法测定患者的CYP3A5,CYP3A4,CYP2D6基因型,并分析每个基因型与羟氯喹血药浓度的关系。结果共有130例患者纳入研究。CYP3A5 (rs776746)各基因型组中,野生纯合子(TT)组、突变杂合子(TC)组、突变纯合子(CC)组的羟氯喹血药浓度分别为(410. 5±112. 2),(1368. 8±218. 3),(1980. 8±644. 7) ng·m L~(-1),3组间差异均有统计学意义(均P <0. 05); CYP3A4 rs28371759基因的突变杂合子组的羟氯喹血药浓度为(8319. 9±7246. 4) ng·m L~(-1),明显高于野生纯合子组(1470. 3±219. 4)ng·m L~(-1),组间差异有统计学意义(P <0. 05)。CYP2D6 rs1065852各基因型组中突变纯合子组(GG组)的羟氯喹血药浓度最高为(2089. 8±479. 4) ng·m L~(-1),野生纯合子组(AA)组血药浓度最低为(1103. 1±198. 9) ng·m L~(-1),差异有统计学意义(P <0. 05)。CYP2D6 rs1135840各基因型组之间的羟氯喹血药浓度分别为(1423. 9±198. 8)和(1716. 0±654. 7) ng·m L~(-1),差异无统计学意义(P> 0. 05)。结论中国SLE患者中CYP3A5*3、CYP3A4*18B、CYP2D6*10基因多态性与羟氯喹血药浓度有关。基因多态性解释不同患者服用相同剂量和频次的羟氯喹表现出波动的血药浓度的原因。建议口服羟氯喹前进行药物基因检测。
Objective To evaluate the correlation between cytochrome P450( CYP) isoforms 3 A4,3 A5,2 D6 genotypes and blood concentrations of hydroxychloroquine( HCQ) in patients with systemic lupus erythematosus( SLE). Methods One hundred and thirty SLE patients taking HCQ for > 1 year were recruited and their blood HCQ concentrations were measured. The CYP3 A4* 18 B,CYP3 A5* 3,and CYP2 D6* 10 genotypes were analyzed by Sanger sequencing. Blood HCQ concentrations and their association with corresponding genotypes was investigated.Results A total of 130 patients were included in the study. The blood concentrations of patients with CYP3 A5 rs776746 wild type homozygous( T/T),heterozygous mutant( T/C) and homozygous mutant( C/C)were( 410. 5 ± 112. 2),( 1368. 8 ± 218. 3),( 1980. 8 ± 644. 7)ng·m L~(-1),there was significant difference in three groups( P < 0. 05). Patients with A/G( rs28371759) CYP3 A4*18 B genotype had significantly higher blood HCQ concentrations( 8319. 9 ± 7246. 4) ng·m L~(-1) than those with the A/A genotype( 1470. 3 ± 219. 4) ng·m L~(-1),the significant difference could be shown in two groups( P < 0. 05). The HCQ was highest in patients with the G/G genotype of the CYP2 D6 * 10 rs1065852 polymorphism( 2089. 8 ± 479. 4)ng·m L~(-1) and lowest in those with the A/A genotype( 1103. 1 ± 198. 9) ng·m L~(-1)( P < 0. 05). And the blood concentration of GG,GC genotypes of CYP2 D6 rs1135840 were( 1423. 9 ± 198. 8) and( 1716. 0 ± 654. 7) ng·m L~(-1). No significant difference could be shown in patients with CYP2 D6 rs1135840 genotypes( P > 0. 05). Conclusion Our study showed that the blood HCQ concentrations was related to CYP3 A5* 3,CYP3 A4* 18 B,CYP2 D6* 10 polymorphisms in China lupus patients taking oral HCQ. CYP polymorphisms may explain why there is wide variation in blood HCQ concentrations. The role of an individual's CYP polymorphisms should be considered when prescribing oral HCQ.
Objective To evaluate the correlation between cytochrome P450( CYP) isoforms 3 A4,3 A5,2 D6 genotypes and blood concentrations of hydroxychloroquine( HCQ) in patients with systemic lupus erythematosus( SLE). Methods One hundred and thirty SLE patients taking HCQ for > 1 year were recruited and their blood HCQ concentrations were measured. The CYP3 A4* 18 B,CYP3 A5* 3,and CYP2 D6* 10 genotypes were analyzed by Sanger sequencing. Blood HCQ concentrations and their association with corresponding genotypes was investigated.Results A total of 130 patients were included in the study. The blood concentrations of patients with CYP3 A5 rs776746 wild type homozygous( T/T),heterozygous mutant( T/C) and homozygous mutant( C/C)were( 410. 5 ± 112. 2),( 1368. 8 ± 218. 3),( 1980. 8 ± 644. 7)ng·m L~(-1),there was significant difference in three groups( P < 0. 05). Patients with A/G( rs28371759) CYP3 A4*18 B genotype had significantly higher blood HCQ concentrations( 8319. 9 ± 7246. 4) ng·m L~(-1) than those with the A/A genotype( 1470. 3 ± 219. 4) ng·m L~(-1),the significant difference could be shown in two groups( P < 0. 05). The HCQ was highest in patients with the G/G genotype of the CYP2 D6 * 10 rs1065852 polymorphism( 2089. 8 ± 479. 4)ng·m L~(-1) and lowest in those with the A/A genotype( 1103. 1 ± 198. 9) ng·m L~(-1)( P < 0. 05). And the blood concentration of GG,GC genotypes of CYP2 D6 rs1135840 were( 1423. 9 ± 198. 8) and( 1716. 0 ± 654. 7) ng·m L~(-1). No significant difference could be shown in patients with CYP2 D6 rs1135840 genotypes( P > 0. 05). Conclusion Our study showed that the blood HCQ concentrations was related to CYP3 A5* 3,CYP3 A4* 18 B,CYP2 D6* 10 polymorphisms in China lupus patients taking oral HCQ. CYP polymorphisms may explain why there is wide variation in blood HCQ concentrations. The role of an individual's CYP polymorphisms should be considered when prescribing oral HCQ.
引文
[1]ALARCN G S,MCGWIN G,BERTOLI A M,et al.Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus:Data from LUMINA,a multiethnic US cohort(LUMINA L)[J].Ann Rheum Dis,2007,66(9):1168-1172.
[2]SHINJO S K,BONFE,WOJDYLA D,et al.Antimalarial treatment may have a time-dependent effect on lupus survival:data from a multinational Latin American inception cohort[J].Arthritis Rheum,2010,62(3):855-862.
[3]COSTEDOAT-CHALUMEAU N,LEROUX G,PIETTE J-C,AMOURA Z H.Antimalarials and systemic lupus erythematosus.[M].5th edition.Rio de Janeiro:Elsevier,2010:1061-1081.
[4]于泽,钟雪,李泰锋,等.高效液相色谱法测定人全血中HCQ浓度[J].中国临床药理学杂志,2017,33(11):1013-1015.
[5]RUDNICKI R D,GRESHAM G E,ROTHFIELD N F.The efficacy of antimalarials in systemic lupus erythematosus[J].J Rheumatol,1975,2(3):323-330.
[6]THE CANADIAN HYDROXYEHLOROQUINE STUDY GROUP.Arandomized study of the effect of withdrawlmg hydroxyehloroquine sulfate in systemic lupus erythematosus[J].N Engl J Med,1991,324(3):150-154.
[7]COSTDOAT-CHALUMEAU N,AMOURA Z,HULOT J S,et al.Low blood concenration of hydroxychloroquine is a marker for and prediction of disease exacerabations in patients with systemic lupus erythematosus[J].Arthrits Rheum,2006,54(10):3284-3290.
[8]COSTEDOAT-CHALUMEAU N,TAMIROU F,LE G V,et al.Blood concentration of hydroxychloroquine in systemic lupus erythematosus care:Usefulness and limits[J].Rev Med Interne,2017,38(2):77-80.
[9]COSTEDOAT-CHALUMEAU N,GALICIER L,AUMAITRE O,et al.Hydroxychloroquine in systemic lupus erythematosus:results of a French multicentre controlled trial(PLUS Study)[J].Ann Rheum Dis,2013,72(11):1786.
[10]DURCAN L,CLARKE W A,MAGDER L S,et al.Hydroxychloroquine blood levels in systemic lupus erythematosus:clarifying dosing controversies and improving adherence[J].J Rheumatol,2015,42(11):2092-2097.
[2]SHINJO S K,BONFE,WOJDYLA D,et al.Antimalarial treatment may have a time-dependent effect on lupus survival:data from a multinational Latin American inception cohort[J].Arthritis Rheum,2010,62(3):855-862.
[3]COSTEDOAT-CHALUMEAU N,LEROUX G,PIETTE J-C,AMOURA Z H.Antimalarials and systemic lupus erythematosus.[M].5th edition.Rio de Janeiro:Elsevier,2010:1061-1081.
[4]于泽,钟雪,李泰锋,等.高效液相色谱法测定人全血中HCQ浓度[J].中国临床药理学杂志,2017,33(11):1013-1015.
[5]RUDNICKI R D,GRESHAM G E,ROTHFIELD N F.The efficacy of antimalarials in systemic lupus erythematosus[J].J Rheumatol,1975,2(3):323-330.
[6]THE CANADIAN HYDROXYEHLOROQUINE STUDY GROUP.Arandomized study of the effect of withdrawlmg hydroxyehloroquine sulfate in systemic lupus erythematosus[J].N Engl J Med,1991,324(3):150-154.
[7]COSTDOAT-CHALUMEAU N,AMOURA Z,HULOT J S,et al.Low blood concenration of hydroxychloroquine is a marker for and prediction of disease exacerabations in patients with systemic lupus erythematosus[J].Arthrits Rheum,2006,54(10):3284-3290.
[8]COSTEDOAT-CHALUMEAU N,TAMIROU F,LE G V,et al.Blood concentration of hydroxychloroquine in systemic lupus erythematosus care:Usefulness and limits[J].Rev Med Interne,2017,38(2):77-80.
[9]COSTEDOAT-CHALUMEAU N,GALICIER L,AUMAITRE O,et al.Hydroxychloroquine in systemic lupus erythematosus:results of a French multicentre controlled trial(PLUS Study)[J].Ann Rheum Dis,2013,72(11):1786.
[10]DURCAN L,CLARKE W A,MAGDER L S,et al.Hydroxychloroquine blood levels in systemic lupus erythematosus:clarifying dosing controversies and improving adherence[J].J Rheumatol,2015,42(11):2092-2097.