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

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。

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

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(P>0.05).For C3435T,there was no significant pharmacokinetic parameters differences among different genetype subgroups(P>0.05).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.