Influence Of Cytochrome P450 Gene Polymorphism On The Pharmacokinetics Of Single Quetiapine In Chinese Healthy Volunteers

Objective:To investigate the effect of CYP3A4*18B and CYP3A5*3 gene polymorphism on the pharmacokinetics of quetiapine in Chinese healthy volunteers on fasting and postprandial.Methods:1.According to the inclusion criteria,67 healthy Chinese volunteers were enrolled,including 34 in the fasting group and 33 in the postprandial group.All of volunteers passed the overnight fasting for at least 10 h.The postprandial group of subjects finished a high-fat,high-calorie standard diet within 30 minutes.Two groups of volunteers were given a single dose of 25 mg of quetiapine tablets.Blood samples were collected at different time points according to the test protocol.The blood concentration of quetiapine was analyzed by the verified LC-MSIMS method,and the pharmacokinetic parameters were estimated by WinNonlin 6.3 software.2.The Sanger method was used to detect the genes of CYP3A4*18B and CYP3A5*3 in 67 healthy subj ects involved in the pharmacokinetic study of quetiapine.3.The analysis was performed by SPSS 20.0 and Gradpad software.The measurement data were expressed as mean ± standard deviation(x±s).The X2 test detected whether the allele and genotype distribution accorded with Hardy-Weinberg equilibrium;Cmax and Tmax were measured values,and Cmax,AUC0-t and AUC0-?were analyzed by logarithmic transformation and ANOVA analysis was performed.Tmax was analyzed by the nonparametric test.P value<0.05 was considered statistically significant.Results:1.Among 67 healthy volunteers,there were 37(55.22%)cases of 20230G>A-CC,27(40.30%)cases of 20230G>A-CT,3(4.48%)cases of 20230G>A-TT and 5(7.46%)cases of 6986A>G-AA,27(40.30%)cases of 6986A>G-AG,35(52.24%)cases of 6986A>G-GG.There were 67(100.00%)cases of CYP3 A4*18B-20070T>C.The CYP3 A4*18B-20230G>A and CYP3A5*3-6986A>G genotype distributions are consistent with the Hardy-Weinberg genetic equilibrium law.2.In the fasting group the Cmax of 6986A>G-AA,6986A>G-AG and 6986A>G-GG were(35.03±4.41)ng·mL-1,(111.06±33.46)ng·mL-1 and(93.66±41.25)ng·mL-1 respectively.The Cmax of 6986A>G-GG and 6986A>G-AG was statistically significant difference of 6986A>G-AA(P<0.05).The AUC?of 6986A>G-AA,6986A>G-AG and 6986A>G-GG were(135.49±27.65)ng·mL-1·h-1,(3 16.97±119.94)ng.ml-1·h-1,and(288.22±133.82)ng·ml-1·h-1 respectively.The AUC0-t of 6986A>G-AG,6986A>G-GG was statistically significant difference of 6986A>G-AA(P<0.05).The AUC0-? of the 6986A>G-AA,the 6986A>G-AG and the 6986A>G-GG were(144.67±28.18)ng·ml-1·h-1,(328.57±122.08)ng·mL-1·h1 and(300.83±139.27)ng·mL-1·h-1 respectively.The AUC0-? of 6986A>G-AG,6986A>G-GG was statistically significant difference of 6986A>G-AA(P<0.05).There was no statistically significant difference in Cmax,Tmax,AUC0-t,AUC0-? and t1/2 between 20230G>A-CC and 20230G>A-CT/TT.3.In the postprandial group,there were no significant differences in Cmax,Tmax,AUC0-?,AUC0-? and ti/2 between 6986A>G-AA group,6986A>G-AG group and 6986A>G-GG group.There was no statistically significant difference in Cmax,Tmax,AUC0-t,AUC0-? and t1/2 between 20230G>A-CC,20230G>A-CT and 20230G>A-TT.4.The Cmax of the fasting group and the postprandial group were(95.14±41.40)ng mL-1and(65.79±38.45)ng mL-1 respectively and the difference was statistically significant(P<0.05).The Tmax of the fasting group and the postprandial group were(0.82±0.34)h and(3.12±1.57)h respectively and the difference was statistically significant(P<0.05).The AUC0-t of the fasting group and the postprandial group were(285.73±128.95)ng·mL-1·h-1 and(357.32±150.91)ng·mL-1·h-1 respectively and the difference was statistically significant(P<0.05).The AUC0-? of the fasting group and the postprandial group were(297.66±132.78)ng·mL-1·h-1 and(373.31±151.45)ng·mL-1·h-1 and the difference was statistically significant(P<0.05).There was no statistically significant difference in t1/2 between the fasting group and the postprandial groupConclusion:1.The pharmacokinetic parameters Cmax,AUC0-t and AUC-? of quetiapine tablets in vivo may be related to the CYP3A5*3-6986A>G gene polymorphism,and the clinical significance of heredopharmacology needs further study.The study will provide the basis for individualization of quetiapine2.The high-fat diet affects the changes of pharmacokinetic parameters Cmax,Tmax,AUC0-t and AUC0-? in quetiapine tablets,and significantly promotes the absorption of quetiapine in healthy volunteers with CYP3A4*18B genotype and CYP3A5*3 genotype.