Population Pharmacokinetic Of Metoprolol In China Patients After PCI

Purposes1.To establish the population pharmacokinetics of metoprolol in patients with coronary heart disease after percutaneous coronary intervention in China by non-linear mixed effect model.The pharmacokinetics model provides a reference for the individualized treatment of metoprolol.2.To explore the effect of CYP2D6*10 gene mutation on the pharmacokinetic parameters of metoprolol.Method1.To detect CYP2D6*1/*10 genotyping by gene chip method.2.Metoprolol plasma concentrations were determined by Liquid chromatography tandem mass spectrometry?LC-MS/MS?.3.One-compartment model was used to establish MET's PPK model using NONMEM software to quantitatively examine the pharmacokinetic parameters of MET in 43 patients including gender,age,liver and kidney function,CYP2D6 gene mutation,combined medication,and comorbidities.influences.4.The goodness of the model was evaluated by the evaluation model.The stability and internal validity of the metoprolol pharmacokinetic model were investigated by the nonparametric bootstrap method.At the same time,the normalization prediction distribution error?NPDE?was used to investigate the distribution error metoprolol pharmacokinetic model predictability and whether it can generate simulation Data.Result1.The frequency of CYP2D6 gene and genotype distribution in 43 cases of postoperative coronary heart disease patients:CYP2D6*1/*1:18.61%?8 cases?,CYP2D6*1/*10:51.16%?22 cases?,CYP2D6*10/*10:30.23%?13 cases?;*1:44.19%,*10:55.81%.The frequency of genotype distribution conforms to Hardy-Weinberg equilibrium.2.LC-MS/MS method for determination of MET plasma concentration standard curve regression equation is Y=7.98*103*X+313?n=8,r=1.0000?,linear range0.5-100ng.ml-1,detection limit is 0.33 ng.mL^-1?S/N=10?.The extraction recovery rate was 97.6-103.5%,and the intraday precision and interday precision were all less than 5%,and the matrix effect was 1.05-1.18.3.The final PPK model of MET based on 92 blood drug concentration points,CYP2D6 genotypes,combination medication,complications and other relevant data of 43 patients with coronary heart disease after PCI was:CL/F(L?h^-1)=?_CL*ICYP*e^?V/F?L?=?_VThe final model showed that only the CYP2D6 gene mutation had an effect on the MET clearance rate,which showed that the CYP2D6*10 mutation could reduce the MET clearance rate.Compared with the CYP2D6*1/*1 genotype,the clearance rate of the CYP2D6*1/*10 genotype decreased by 36.6%.Compared with the CYP2D6*1/*1 genotype,the clearance rate of the CYP2D6*10/*10 genotype decreased by 70.7%,indicating a gene dose effect.No covariates were found that had an effect on the apparent clearance of MET.4.The scatterplot fitting degree of the final model is better than the simplest model;the non-parametric bootstrapping method has an internal verification stability of99.2%,and the relative deviation is less than 10%,suggesting that the model has good stability and internal efficiency.NPDE homogeneity of variance obey normal distribution,suggesting that the model has good predictive ability and can generate simulation data.Conclusion1.This study used LC-MS/MS method to detect MET plasma concentration with high sensitivity,high selectivity,and good accuracy.It provided a reliable method for clinical metoprolol concentration determination and pharmacokinetic study.2.CYP2D6*10 gene mutation is an important factor affecting the MET clearance rate.The PPK model of MET established in this study is stable and reliable and can provide reference for individualized administration of metoprolol.