多药耐药基因多态性与异维A酸人体药代动力学差异关联性研究  

Influence of MDR1 Gene Polymorphisms on Pharmacokinetic Parameters of Isotretinoin in Healthy Male Subjects

作　　者：周可[1,2] 吴黎莉[1] 陈沄[1] 

机构地区：[1]中国医学科学院北京协和医学院皮肤病研究所,南京210042 [2]天津市中医药研究院附属医院

出　　处：《中国中西医结合皮肤性病学杂志》2012年第1期8-13,共6页Chinese Journal of Dermatovenereology of Integrated Traditional and Western Medicine

摘　　要：目的研究多药耐药基因MDR1基因多态性对异维A酸人体药代动力学(药动学)的影响。方法 21例健康男性受试者单次口服40 mg异维A酸胶丸,提取外周血基因组DNA采用等位基因特异扩增法(allele-specificamplification,ASA-PCR)对MDR1外显子(exon)12(C1236T)、exon21(G2677T/A)、exon26(C3435T)位点进行基因分型检测;高效液相色谱-串联质谱法(HPLC/MS)分析受试者异维A酸血药浓度并计算相关药动学参数,比较不同基因型药动学参数差异。结果 MDR1exon12(C1236T)的不同基因型异维A酸的体内某些药动学参数有差异。与野生型组相比,变异型组Cmax、Tmax有所增加,但差异无统计学意义(P值分别为0.057、0.252);AUC 0～60显著提高(P=0.049)、T1/2及MRT明显缩短(P值分别为0.011、0.035)。MDR1exon21(G2677T/A)的不同基因型异维A酸的体内各项药动学参数差异无统计学意义。MDR1 exon26(C3435T)参数T1/2、MRT、AUC 0～60在杂合型组与变异型组之间差异无统计学意义,变异型组Cmax有所增加,差异无统计学意义;变异型组Tmax显著小于杂合型组(P=0.03)。结论MDR1 C1236T变异型组体内异维A酸吸收略有增多,T1/2、MRT缩短,异维A酸的体内代谢明显加快。虽然MDR1G2677T/A及MDR1 C3435T之间存在显著遗传连锁不平衡关系,且对P糖蛋白(P-gp)的功能影响较大,但本研究结果显示这两个位点基因突变对异维A酸的体内过程影响不显著。Objective To evaluated the influence of multi-drug resistance gene 1（MDR1） C3435T,G2677T/ A and C1236T polymorphism on the pharmacokinetics of isotretinoin in 21 heathy male subjects.Methods Blood samples were collected from 21 healthy male subjects who received a single oral dose of 40 mg isotretinoin.The genotypes of MDR1 C3435T,G2677T/A and C1236T of the samples were detected by allele-specific amplification（ASA-PCR）.The pharmacokinetic parameters of isotretonoin were compared between the different genotypes of MDR1 by statistical comparisons method.High performance liquid chromatography-electrospray ionization mass spectrometry（HPLC-MS） was used for the quantification of isotretinoin in human plasma which was standardized by dosage and body weight.Pharmacokinetic parameters were determined by non-compartmental analysis.Results For C1236T,the Cmax,Tmax,AUC 0-60 of carriers with CT and TT was remarkably higher than those with CC（P=0.057,P=0.252,P =0.049,respectively）,the T1/2 and MRT of carriers with CT and TT was remarkably lower than those with CC（P=0.011 and P=0.035）.For G2677T/A,there was no significant pharmacokinetic parameters difference among the different genetype subgroups（P0.05）.For C3435T,there was no significant pharmacokinetic parameters differences among different genetype subgroups（P0.05）.In addition,the Tmax of carriers with CC and CT was higher than those with TT（P=0.03）.Conclusion It suggests that the MDR1 C1236T polymorphism influenced the human absorption of oral isotretinoin.Although there is genetic linage diequilibrium between C3435T and G2677T/A which can influences the isotretinoin absorption,the genetic polymorphisms of MDR1 C3435T and G2677T/ A had no effect to isotretinoin pharmacokinetic parameters in this research.

关 键 词：异维A酸 药代动力学 MDR1 基因多态性 

分 类 号：R285[医药卫生—中药学]