A Meta-Analysis About The Effect Of CYP2D6 Gene Polymorphisms And ADRB1 389 Locus Gene Polymorphisms On Metoprolol Pharmacokinetics And Pharmacodynamics

Objective:To evaluate the effect of cytochrome P450 2D6（CYP2D6）gene polymorphism on the metabolism and efficacy of metoprolol.At the same time,the influence of the polymorphism of the adrenalin receptor（ADRB1）gene at 389（rs 1801253）on the efficacy of the drug was evaluated.Methods:Searching all relevant studies on the effect of CYP2D6 and metoprolol pharmacokinetics and pharmacodynamics or ADRB1 389 locus（rs1801253）polymorphisms on metoprolol pharmacodynamics was performed by using the CNKI,VIP,WanFang,and Web of science（SCIE）,Embase and PubMed databases since the establishment of the database.The literature was screened and included into the quality evaluation,and the literature data was extracted.RevMan 5.3 was used to conduct quantitative Meta-analysis on the outcome indicators of all included literatures.Results:Part I（CYP2D6 and metoprolol）:A total of 7 references were included in pharmacokinetic studies,including 124 cases in the non-PM group and 42 cases in the PM group.AUC_0-∞of PM was significantly higher than that of non-PM group,and the difference between groups was statistically significant（p<0.00001）.The metoprolol C_maxax in PM group was significantly higher than that in non-PM group（p<0.00001）,and was higher than that in EM,IM and UM groups（p<0.00001,p<0.0001,p<0.00001）.T_1/2/2 of PM group was higher than that of non-PM group（p<0.00001）,and t_1/2/2 of PM group was higher than that of EM,IM and UM group（p=0.0002,p<0.00001,p=0.005）.CL/F of PM group was significantly lower than that of non-PM group（p<0.00001）,and both PM group were lower than EM and UM group（p<0.00001,p=0.0004）.A total of 8 references were included in the pharmacodynamics study,including 631 cases in the non-PM group and 206 cases in the PM group.The SBP reduction in the PM group was larger than that in the non-PM group,with no statistically significant difference（p=0.20）.The SBP reduction in the IM group was larger than that in the EM group,with statistically significant difference（p=0.03）.The effect of DBP reduction in PM group was larger than that in non-PM group,with statistically significant difference（p=0.01）.The value of DBP reduction in EM group was lower than that in IM group,with significant difference on statistic（p=0.02）.The decreased HR value of non-PM group was larger than PM group,with statistically significant difference（p=0.05）.The decreased HR value of IM group was larger than that of EM group（p=0.002）.PartⅡ（ADRB1 and metoprolol）:A total of 5 studies were included,including 317 Gly389 carriers（GG+GC）and 250 Arg389 homozygotes（CC）.The reduction of systolic blood pressure（SBP）level in the gene type of CC was greater than that in GG+GC（p=0.01）.But there was no statistical difference between the wild type GG and the mutant heterozygous type GC（p=0.77）;The reduction of diastolic blood pressure（DBP）level in the gene type of CC was significantly greater than that in GG+GC（p=0.0003）,but no statistical difference between the GG and the GC（p=0.68）;The reduction of heart rate（HR）level in the gene type of CC was significantly greater than that in GG+GC（p=0.0006）,but no statistical difference between the wild type GG and the GC（p=0.49）.Conclusion:The influence of CYP2D6 on metoprolol has been confirmed in the part of pharmacology that compared with UM,EM and IM groups,the PM metabolome has better bioavailability and longer metabolic clearance time.Further included in the pharmacodynamic study,it was found that the antihypertensive effect of the PM group was better than that of the non-pm group（UM,EM and IM group）,and the difference was more obvious in the control of DBP,while the efficacy of the PM group was weaker than that of the non-pm group in the control of heart rate.In ADRB1 gene,metoprolol had better efficacy in the mutant homozygous CC population,while wild type GG and mutant heterozygous type GC had no difference in the efficacy of metoprolol.