多药耐药基因多态性和单倍体对环孢素A血药浓度的影响  

C3435T genetic polymorphisms in MDR1 gene and cyclosporine pharmacokinetics in healthy subjects

作　　者：梁惠琪[1] 焦正[1] 丁俊杰[1] 李中东[1] 施孝金[1] 钟明康[1] 

机构地区：[1]复旦大学附属华山医院临床药学研究室,上海200040

出　　处：《中华检验医学杂志》2005年第12期1235-1238,共4页Chinese Journal of Laboratory Medicine

基　　金：上海市卫生局百人计划资助项目(98BR009)

摘　　要：目的探讨中国健康志愿者中多药耐药基因(MDR1)12外显子C1236T、21外显子G2677T/A和26外显子C3435T多态性及3个位点单倍体连锁不均衡性对环孢素A(CsA)药代动力学特性的影响。方法高效液相色谱法(HPLC)测定20名健康男性单次口服CsA500mg后,24h中不同时间点的血药浓度。采用聚合酶链反应(PCR)结合基因测序法测定3个位点的基因多态性和单倍体类型。结果20名男性健康志愿者中,C1236T位点1名为CC型,8名为CT型,11名为TT型;G2677A/T位点4名为GG型,7名为GT型,4名为AT型,5名为TT型;C3435T位点5名为CC型,11名为CT型,4名为TT型;MDR1的C1236T和G2677A/T的基因多态性与峰浓度(Cmax)和药时曲线下面积(AUC0inf)差异均无统计学意义(均P>0.05),C3435T的基因多态性与Cmax无相关性(P>0.05),而与AUC0inf相关(P<0.05)。CC型、CT型和TT型的Cmax分别为2124.7±179.4ng/ml、1934.2±372.8ng/ml和1765.2±415.6ng/ml;AUC0inf分别为13922.4±2881.5ng/h-1·ml、11511.8±2192.1ng/h-1·ml和8514.9±1063.4ng/h-1·ml;至少含有1个C等位基因的基因型(CC型和CT型),二者的AUC0inf比TT型增高49%。单倍体分析表明,26与12和21外显子间存在单核苷酸多态性的连锁不均衡性,不同单倍体类型对CsA药动力学特性无影响(P>0.05)。结论MDR1C3435T的多态性可能是口服CsA后,生物利用度变异大的影响因素。Objective To determine the effect of C1236T, G2677T/A and C3435T, the single nucleotide polymorphisms （SNPs） in exon 12, 21 and 26 of the human muhidrug resistant gene （MDR1）, and MDR1 haplotypes on cyclosporine （CsA） pharmacokinetic （PK） parameters among healthy Chinese volunteers. Methods The oral CsA PK study was performed on 20 healthy subjects. Blood CsA concentrations were measured by HPLC. The C1236T, G2677T/A and C3435T SNPs were determined by PCR and sequencing analysis. Results In these 20 healthy volunteers, there were one homozygous CC, eight heterozygous CT, and eight homozygous TT for C1236T, four homozygous GG, seven heterozygous GT, four heterozygous AT, and five homozygous TT for G2677T/A, five homozygous CC, eleven heterozygous CT, and four homozygous TT for C3435T. There was no statistical difference between Cmax, AUC and C1236T, G2677T/A SNPs （P 〉 0. 05 ）. There was also no statistical difference between Cmax and C3435T SNPs （ P 〉 0. 05 ）, while there was significant statistical difference between AUC0.ia and C3435T SNPs （P 〈0.05）. According to their genotypes, the mean Cmax and mean AUC0.1a was 2 124. 7 ± 179.4 ng/ml and 13 922.4±2 881.5 ng/h^-1· ml in CC group, 1 934.2 ±372.8 ng/ml and 11 511.8 ± 192. 1 ng/h^-1 .ml inCT group, 1 765.2 ＋415.6 ng/ml and 8 514.9 -＋ 1 063.4 ng · h/ml in TT group, respectively. AUC0-int in CC and CT group was 49% larger than that in TT group. Haplotypes analysis demonstrated that a linkage disequilibrium exists between SNPs in exon 26 and exon 12, 21. MDR1 haplotypes did not affect the pharmacokinetics of cyclosporine （P 〉 0.05 ）. Conclusion The MDR1 C3435T genotype offers a potential mechanistic basis to explain inter-subject difference in CsA oral bioavailability.

关 键 词：环孢素A 糖蛋白类 多药耐药基因 单倍体 

分 类 号：R96[医药卫生—药理学]