A Population Pharmacokinetic And Pharmacodynamic Study Of OATP1B1 Gene Polymorphism Related To Hypo Glycemic Drugs Repaglinide In Groups Of Drugs In Patients With Type 2 Diabetes

Objective:Analysis of factors that may affect the plasma concentration difference of repaglinide in type 2 diabetic patients,Using the NONMEM method,a population pharmacokinetic model in repaglinide in vivo of patients with type 2 diabetes mellitus,evaluation of intra and inter individual differences in drug metabolizing enzymes,transporters to quantify the genetic polymorphism of repaglinide in patients affected the distribution and metabolism,for clinical implementation of individualized medication reference.Methods:1)Establishing quantitative analysis method of HPLC-MS/MS to measure human plasma of repaglinide.2)Were collected in patients with type 2 diabetes treated with repaglinide has reached steady state,blood samples were collected after informed consent,determination of plasma concentration in samples collected with the determinationofrepaglinide,andallpatientswith CYP2C8*3（rs10509681）,UGT1A1*6（rs4148323）,CYP3A4*1G（rs2242480）,OATP1B1*388（rs2306283）and OATP1B1*521（rs4149056）gene polymorphism.3)Will be measured by the blood concentration data test in patients with repaglinide,combined with the corresponding with basic demographic information,clinical information and genotyping and other covariates,the final construction of repaglinide in a population pharmacokinetic model in patients with type 2 diabetes by NONMEM software.Results:1)The quantitative repaglinide concentration developed in this experiment to detect the plasma HPLC-MS/MS analysis method in the index of investigation are good,the result is accurate and reliable.2)This study collected 87 cases of patients with type2 diabetes treated with repaglinide has reached steady state,of which 8 cases did not follow the doctor’s advice to take medicine on time,the remaining 79 patients,46 were male,38 were female,the average age was 58.84+10.81 years old,the average height is 1.63+0.09m,the average weight was 63.09.10.60kg,the average value of BMI was23.64+2.87.The determination results of genotypes showed that UGT1A1*6 genotype in 51 cases,single mutation genotype in 20 cases;double mutations in 8 cases;CYP3A4*1G gene mutation type in 43 cases,single mutation genotype in 33 cases;double mutations in 3 cases;OATP1B1*388 mutation genotype 4 patients,single mutation genotype in 37 cases,double mutations in 38 cases;no OATP1B1*521genotype in 59 cases,single mutation genotype in 16 cases,double mutations in 4 cases;CYP2C8*3 mutant;3)Model shows that the prediction with individual columns Nai values good correlation with the measured PPK model to predict the drug concentration and specimen sampling time and conditions weight residuals（CWRES）without obvious bias,the prediction error most concentration at 2 times the standard deviation（SD）between the table The predictive concentration of the basic model is more accurate.Through the forward tolerance method is found in a population pharmacokinetic model of repaglinide,in addition to have significant effects on the gene polymorphism of OATP1B1*521 metabolic coefficient CLREP on repaglinide（P<0.05）,the gene polymorphism of UGT1A1*6,CYP3A4*1G and OATP1B1*388 added in the model and other covariates on any of the parameters showed no significant difference（P>0.05）.But in the model of reverse elimination process,have significant influence of gene polymorphism of OATP1B1*521 metabolism coefficient CLREP on repaglinide（P<0.05）and other covariates,there were no significant differences in any parameter（P>0.01）.The final model is CL=14.5*CLOP2*e 1（L/H）（when the genotype is TT or TC when CLOP2 is 1,when the genotype CC CLOP2 0.62）.Glycated hemoglobin was used as a pharmacodynamic index,and the correlation model of pharmacodynamic pharmacodynamics was HBC=S₀*e^-γ*AUC0-inf+S_SS*(1-e^-γ*AUC0-inf).Conclusion:1)Quantitative analysis method established in this study HPLC-MS/MS detection in human blood repaglinide concentration had good specificity and sensitivity,the measurement results are accurate and reliable.2)This study successfully constructed repaglinide in a population pharmacokinetic model in patients with type two diabetes,the diagnosis results are good model.Effects of covariates showed that the gene OATP1B1*521 polymorphism may affect the pharmacokinetics of repaglinide in patients with type two diabetes.