Meta - Analysis Of Metabolic Metabolism Of Metoprolol And The In Vitro Metabolic Activity Of New Subtypes

Objective:Using Meta-analysis systematically review related literature about the effect of CYP2D6 enzyme activity on the pharmacokinetics and pharmacology of metoprolol and systematic evaluation of its impact to provide guidance for clinical decision. In this vitro study, the new Alleles metabolic activity of CYP2D6* 34,* 106,* 107 which were found higher frequency in Chinese Uighur were evaluated. Aimed to explore the CYP2D6 gene mutations whether affects the expression of its enzyme to provide a basis for optimizing the clinical dose and experiment foundation.Methods:1. A Meta-Analysis about the effect of CYP2D6 enzyme activity on the pharmacokinetics and pharmacodynamics of metoprolol.CNKI, VIP, WanFang Data, PubMed databases were electronically searched for published articles on the effect of CYP2D6 enzyme activity on the pharmacokinetics and pharmacology of metoprolol from inception to January 2015. After independently screening literature by two investigators, datas were extracted and assessed the quality of included studies by using the Cochrane methods and GRADE.Then, meta-analysis was performed using RevMan 5.3and Comprehensive Meta Analysis V2 software in AUC0-∞, Cmax, t1/2, CL/F, heart rate, systolic blood pressure, diastolic blood pressure.2. CYP2D6 new Alleles differences in vitro analysis.Plasmids carrying the CYP2D6 wild-type were used as the template to generate CYP2D6*34, CYP2D6*106, CYP2D6*107. Using Site-directed Mutagenesis method, Double Digestion, T4 DNA Ligase chain reaction and E.coli DH5α transformation method successful constructed eukaryotic expression vector mutagenesis of p3XFLAG-CMV-14-CYP2D6*34,P3XFLAG-CMV-14-CYP2D6*106, p3XFLAG-CMV-14-CYP2D65*107. Western blot was performed to CYP2D6*34, CYP2D6*106, CYP2D6*107 protein expression.Results:1.7 studies were included involving 567 volunteers. The results of meta-analysis were AUC0-∞ (RR=-6.75,95%CI-9.18 to -4.31, P<0.00001), Cmax(RR=-2.40,95% CI-3.25 to -1.54,P<0.00001),t1/2 (RR=-4.81,95%CI -6.86 to -2.76, P<0.00001), CL/F (RR=1.60,95%CI 1.03 to 2.17, P<0.00001), heart rate (RR=1.48,95%CI 0.03 to 2.92, P=0.05), systolic blood pressure (RR=-0.69, 95%CI-1.85 to 0.47, P=0.24), and diastolic blood pressure (RR=-1.95,95%CI-3.14 to -0.76, P=0.001). The results of Begg test were not significant (P>0.05). Pharmacokinetic parameters Egger test were significant (P<0.05). Pharmacodynamics parameters Egger test were not significant (P>0.05).2. The expression levels of CYP2D6*34 is 68.71% of CYP2D6 wild-type. The expression levels of CYP2D6*106 is 87.07% of CYP2D6 wild-type. Compared to the wild-type CYP2D6, both have no statistically significant differences. But the protein expression levels of CYP2D6*107 is 42.18% of CYP2D6 wild-type. Compared with wild type CYP2D6 enzyme activity, CYP2D6*107 protein expression level is slightly decreased.Conclusion:CYP2D6 enzyme activity effects on AUC0-∞, Cmax, t1/2, CL/F, heart rate, diastolic blood pressure. However, systolic blood pressure is not associated with CYP2D6 enzyme activity. CYP2D6*107 is apparently decreased CYP2D6 protein expression level. CYP2D6*34, CYP2D6*106 do not significantly affect CYP2D6 protein expression level.