Study On Population Pharmacokinetic Of Meropenem And Multi-resistant Genes C3435T Polymorphism

Objective1. To establish the PPK model of MEPM in Chinese population, and provide the basis for individualized medication.2. To discuss the effect of MDR1 C3435 T polymorphism on the pharmacokinetics of meropenem.Method1. Determine blood concentrations of MEPM by HPLC-UV.2. Determine genotypes of the MDR1 C3435 T polymorphism by Polymerase Chain Reaction- restriction fragment length polymorphism?PCR-RFLP?.3. The study involved the cases of hospitalized patients receiving MEPM therapy,record sex, age, body weight, hepatorenal function and co-administration et al.collecting concentrations which have reached steady state blood samples. To determine the MEPM serum concentrations by HPLC-UV.4. Evaluate the the random effects and fixed effects on the clearance rate of MEPM by nonlinear mixed effects mode and the full amount of regression models of MEPM was established by stepwise regression, and the final model was build via the backward regression.5. Evaluate the model fitting by plots, stability and internal validity of the model was evaluated by Bootstrap, the predictive ability of the model was evaluated by normalized predictive distribution error?NPDE?.Result1. Determined by the HPLC-UV detection with the equation:0516.0-X259.0Y??28??R=0.9998?,the linearity was good within the range of0.231-92.5?g·m L^-1?n=7?. At three concentration, the extraction recoveries was67.53%-75.03%, the recoveries was 98%^-105%, the intra and inter-day RSD was lessthan 5%, the detection limit was 0.1?g·m L^-1?S?N?3?.2. MDR1 C3435 T genotype frequency and patients number of 101 patients: CC type 39 cases?38.6%?, the CT type 48 cases?47.5%?, TT type 14 cases?13.9%?.Comparing the actual value and the theoretical value of the distribution of gene frequency of three groups by SPSS 16.0, there was no statistically significant difference?p>0.05?.3. Base on 173 concentrations of the 101 patients, the PPK final regression model of MEPM was established, as follow:CL=14.3×?CLcr/120?^0.427×e^0.366(L·h^-1)24.9=V?L?Conclusion1. HPLC method is suitable for therapeutic drug monitoring of meropenem with good accuracy, high sensitivity and convenient operation.2. The determination of genotypes of the C3435 T polymorphism by polymerase chain reaction?PCR?followed by restriction fragment length polymorphism?RFLP?was feasible.3. The PKK model of MEPM is established in the present study is of great stability and predictive ability, which could provide individualized dosage regimens.