The Influence Of P450 2D6 Genetic Polymorphism On The Pharmacokinetics Of Metoprolol In Chinese Han Population In North China

OBJECTIVE:Drug metabolism is one of critical factors eliminated in body,liver is its main organ of metabolism,cytochromeP450(CYP450) is one of important metabolic enzymes,however,with diversities of regions,races,heredity and personalities,it shows gene polymorphism leading to marked individual variation to drug metabolism.As a result,different effects and adverse reactions happen to patients.The study of the relationship of P450 2D6 gene polymorphism and the pharmacokinetics of metoprolol in Chinese Han population in North China to evaluate the effects of different mutational sites on enzymatic activity has been carried out.METHODS:P450 2D6 genotype was determined by oligonucleotide microarray.P450 2D6 phenotype were evaluated in 40 healthy individuals expressing the CYP 2D6^*2W^* 10W, CYP 2D6^*2H^*10W or CYP 2D6^*2M^*10W,CYP 2D6^*2M^*10H and CYP 2D6^*2M^*10M genotypes(W:widetype;M:mutant type;H:heterozygote)using metoprolol as a probe of P450 2D6 activity.Plasma and urine samples were collected from each subject over a 24-hour period after administration of 100 mg metoprolol tablet.The metoprolol and one of its metabolitesα-hydroxymetoprolol concentrations were determined by HPLC with fluorescence detection in human plasma and urine,then the pharmacokinetic parameters were calculated by Drug And Statistics for Windows to explore the relationship of P450 2D6genetic polymorphism and the pharmacokinetics of metoprolol in Chinese Han population in North China.RESULTS:The main pharmacokinetic parameters of metoprolol andα-hydroxymetoprolol were significantly different between subjects with the CYP 2D6^*2W^* 10W allele and those for the CYP 2D6^*2M^* 10H and CYP 2D6^*2M^* 10M mutant allele respectively,I.e,Metoprolol andα-hydroxymetoprolol AUC_0-24,AUC_0-∞,AUMC_0-24,AUMC_0-∞,Cmax and t_1/2 of subjects with the CYP 2D6^*2M^*10H and CYP 2D6^*2M^*10M were significantly increased than those for CYP 2D6^*2W^*10W respectively(P＜0.05),Metoprolol andα-hydroxymetoprolol AUC_0-24,AUC_0-∞,AUMC_0-24,AUMC_0-∞,Cmax,t_1/2 of subjects with the CYP 2D6^*2M^*10M were significantly increased than those for the CYP 2D6^*2M^*10H(P＜0.05)。CONCLUSIONS:P450 2D6genetic polymorphism has an impact on metabolic enzymes of Metoprolol in Chinese Han population in North China.The P450 2D6 activity was significantly reduced in the CYP2D6^*2M^*10H or CYP 2D6^*2M^*10M compared with CYP 2D6^*2W^*10W respectively,and the P450 2D6 activity was more severely impaired in CYP 2D6^*2M^*10M compared with CYP 2D6^*2M^*10H.In short,genetic polymorphism of CYP2D6^* 10 has an marked an influence on the pharmacokinetics of Metoprolol,as a result, the P450 2D6 genotype is the major determinant of P450 2D6 phenotype.