MDR1基因多态性对口服环孢素A药代动力学的影响  

Effect of MDR1 polymorphic expression on oral disposition of cyclosporine A

作　　者：焦正[1] 梁惠琪[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：《药学学报》2004年第12期971-974,共4页Acta Pharmaceutica Sinica

基　　金：上海市卫生局百人计划项目II期资助项目(98BR009)

摘　　要：目的　非线性混合效应模型(NONMEM)考察中国健康人多药耐药基因(MDR1)中26外显子的C3435T 多态性与环孢素A(CsA)药代动力学特性间的关系。方法　HPLC法测定20名健康男性单次口服CsA微乳溶液制 剂500mg后24h内不同时间点的药物浓度。MDR1的基因多态性测定采用DNA限制性片段长度多态性法,并用基 因测序法验证。数据处理与模型拟合采用NONMEM法。结果　中国健康人中含MDR1C3435TCC或CT型的相对 生物利用度较TT型高40%。结论　MDR1中C3435T多态性是个体间CsA相对生物利用度差异的影响因素。Aim To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 gene and cyclosporine (CsA) pharmacokinetic (PK) parameters among healthy Chinese volunteers by nonlinear mixed effect model (NONMEM). Methods Twenty healthy subjects were given orally a single dose of 500 mg CsA in microemulsion solution. Blood CsA concentrations were measured with HPLC and the genotype for the C3435T polymorphism of MDR1 gene was determined with the PCR and restriction fragment length polymorphism. The results were further confirmed by sequencing. NONMEM was performed to assess the effect of genotype on CsA PK profile. Results MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. The relative bioavailability of CsA was 40% higher in subjects who carried at least one 3435C allele compared to that of TT type individuals in the study population. Conclusion The MDR1 C3435T genotype offers a potential basis of mechanism to explain inter-subject differences in CsA oral bioavailability.

关 键 词：环孢素A P-糖蛋白 多药耐药基因 非线性混合效应模型 

分 类 号：R969[医药卫生—药理学] R979.5[医药卫生—药学]