The Genetic Polymorphism Of CYP3A4, CYP2C9, CYP2C19, CYP2D6 In Different Chinese Population And The Effect Of CYP3A4~*18 On Zolpidem Pharmacokinetics

Objective:We study and compare the C.YP3A4,CYP2C9,CYP2C19 and CYP2D6 allele frequencies in Han,Uighur,Hui and Mongolian Chinese populations.Furthermore,the impact of CYP3A4~*18 genetic polymorphism on the pharmacokinetics of zolpidem was evaluated.The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population.Methods:we randomly evaluated 672 unrelated,healthy Chinese volunteers(Han:136;Mongolian:158;Hui:164;Uighur:214)to compare the CYP3A4,CYP2C9,CYP2C19 and CYP2D6 allele frequencies.Genomic DNA was extracted from peripheral leukocytes and genotyped for CYP3A4~*5,CYP3A4~*18;CYP2C9~*2,~*13;CYP2C19~*2,~*3 and CYP2D~*10 by PCR-restriction fragment length polymorphism analysis(PCR-RFLP).Meta-analysis was used to compare the allele and genotype frequencies in the four races.Blood samples were collected from eight CYP3A4~*1/~*1 genotype subjects,six CYP3A4~*1/~*18 genotype subjects and one CYP3A4:~*18/~*18 genotype subjects.A simple,fast,selective,accurate and precise high-performance liquid chromatographic method coupled with fluorescence detector was developed for the determination of zolpidem concentrations in human plasma.Estimates of pharmacokinetic parameters of zolpidem were obtained from DAS software.The pharmacokinetic parameters of there groups were compared by the methods of Independent-Samples T Test in SPSS,Results:The allele frequencies of CYP3A4/18 in the Han,Mongolian,Hui and Uighur Chinese population were 18.4%,20.3%,19.2%and 14.0%,respectively;In our study,the CYP3A4~*5 allele was not found in the four Chinese populations.The allele frequencies of CYP2C9~*2 in the Han,Mongolian Hui and Uighur Chinese population were 1.10%,2.53%,4.57%and 9.58%,respectively;only one CYP2C9~*1/~*13 genotype was found respectively in Uighur and Mongolian Chinese population in our study,no CYP2C9~*13/~*13 genotype was found in four Chinese population.The allele frequencies of CYP2C19~*2 in the Han,Mongolian,Hui and Uighur Chinese population were 38.6%,41.5%,49.4%and 32.5%,respectively;and the allele frequencies of CYP2C19~*3 were 57.4%,46.5%,39.7%and 22.4%.The allele frequencies of CYP2D6~*10 in the Han,Mongolian,Hui and Uighur Chinese population were 57.4%,46.5%,39.7%and 22.4%,respectively;CYP3A4,CYP2C9,CYP2C19 and CYP2D6 allele andgenotype frequencies resulted in equilibrium with the Hardy-Weinberg equation.The pharmacokinetic parameters of CYP3A4~*1/~*1 genotype and CYP3A4~*1/~*18 and CYP3A4~*18/~*18 genotype healthy subjects were as follows:t1/2:(3.47±0.87),(2.64±0.53)h;Cmax:(170.77±43.53),(174.21 ±44.54)?g·L-1;tmax:(0.84±0.13),(0.96±0.10)h;Vz/F:(84.98±15.66),(72.48±35.80)L;CLz/F:(17.74±4.76),(19.52±10.95)L/h;AUC0-12:(541.82±123.94),(586.12±237.81)?g·L-1·h;AUC0-?:(601.95±167.06),(618.19±250.86)?g·L-1·h.There were no significant differences between the two groups.But the t1/2 of CYP3A4~*1/~*18 and CYP3A4~*18/~*18 genotype healthy subjects was decreasing trend,the CLz/F was increasing trend compared with CYP3A4~*1/~*1 genotype healthy subjects.Sample number was small might give rise to no significant differences between the two groups.Conclusions:The allele of CYP3A4~*5 and CYP2C9~*13 were an exceptional phenomenon.Our study showed that there was no significant ethnic difference in the distribution of CYP2C19~*3 and CYP3A4~*18 in the Han,Mongolian,Hui and Uighur Chinese population;There was no significant ethnic difference in the distribution of CYP2C9~*2 in Han,Mongolian and Hui,but the Uighur was significantly higher than the Han,Hui and Mongolian.For CYP2C19~*2,the Han were not significantly different from the Uighur,Hui,or Mongolian;however,the Uighur was significantly lower than the Hui.For CYP2D6~*10,the Mongolian was not significantly different from the Han and the Hui.However,the Uighur was significantly lower than other three.There were no significant difference between the CYP3A4~*1/~*1 genotype group and CYP3A4~*1/~*18 and CYP3A4~*18/~*18 genotype group.But the t1/2 of CYP3A4~*1/~*18 and CYP3A4~*18/~*18 genotype healthy subjects was decreasing trend,the CLz/F was increasing trend compared with CYP3A4~*1/~*1 genotype healthy subjects.Sample number was small might give rise to no significant differences between the two groups.Our study indicates that that CYP3A4~*18 might accelerate the metabolism of zolpidem in vivo.Further investigations that enlarged sample number were extremely necessary.