Research Of The Population Pharmacokinetic Model Of Rosuvastatin And Multi-Resistant Genes C3435T Polymorphism In Patients

Research Purpose1.To establish the population pharmacokinetics model of RSVT in patients and provide reference for clinical individual administration.2.To discuss the influence of MDR1 C3435 T genetic polymorphisms on plasma concentration of RSVT. Research Methods1.Determine blood concentration of RSVT by UPLC-MS/MS;2.Use PCR-RFLP to detect MDR1 C3435T;3.Construct the population pharmacokinetics model of rosuvastatin by using NONMEM statistic software. Illustrate the influence of patients’ physiological index、MDR1 C3435 T gene type and Combined medication to pharmacokinetics of rosuvastatin. Research Results1.To determine blood concentration of RSVT by UPLC-MS/MS.Standard curve regression equation of rosuvastatin is y=0.08582x-0.05864（ r²=0.9998,n=7）.Concentration range is 0.5²00 ng·m L^-1;Recovery of rosuvastatin is 83.00%⁸8.71%;Method recovery is 92.9%¹04.8%;Intra day and inter day precision is（RSD）<8%;Detection limit is 0.25ng·ml^-1（S/N≥3）.2.In all of the 97 samples,mutation rate of MDR1 C3435 T is 36.08%,specifically, the wild homozygous（CC）alleles frequencies is 40.21%;mutation heterozygous（CT）alleles frequencies is 47.42%;mutation homozygous（TT）alleles frequencies is 12.37%。The distribution of MDR1 C3435 T matched the Hardy-Weinberg law of heredity balanc（p>0.05）.3.Based on 149 blood drug concentration data and related parameters in 97 patients,To establish the population pharmacokinetics model of RSVT,Final regression model of the PPK model of rosuvastatin is:Serum total protein（TP） and serum total bilirubin（TBIL） is the main factor affecting of rosuvastatin clearance（CL / F）, and the combined use of aspirin can affect the apparent volume of RSVT.4.In the present study, we have not found that the MDR1 C3435 T genotype has an effect on the plasma concentration of RSVT. Conclusion1. In this study,we established UPLC-MS/MS method to detect the blood concentration of rosuvastatin. This method is easy to use, reliable and its repeatability is very good, which means this method can be applied to rosuvastatin pharmacokinetic study.2.PCR-RFLP is suitable for MDR1 C3435 T genotyping research, its operation is simple and rapid. Its results are high sensitivity and reliable.3.Serum total protein（TP） and serum total bilirubin（TBIL） is the main factor affecting of rosuvastatin clearance（CL / F）, and the combined use of aspirin can affect the apparent volume of RSVT.4.This research established a stable and reliable PPK model of rosuvastatin and this model can provide reference for clinical rational use of drugs.