| Objective1.To establish HPLC-UV method for determinating human plasma propofolconcentrations.2.To compare and evaluate the performance of Marsh and Schnider parameter modelinserted in target controlled infusion system.3.To establish population pharmacokinetics （PPK） of propofol for gynecologicalpatients.Method1.HPLC-UV on propofol.chromatographic column,Waters Nova-pak C18（3.9×150mm,4μm）.Mobile phase,carbinol-water （0.8:0.1,V/V）.Flow velocity,0.9mL·min-1.Measurement wavelength,270nm.Column temperature,30℃.2.Conform to the collection standards,gynecological patients were divided into Marshand Schnider group under general anesthesia with TCI system by random numbertable.All samples were determined by HPLC-UV method.Comparing the difference ofmeasured and predicted concentrations in Marsh and Schnider group by SPSS19.0software using ANOVA for repeated measurement,to evaluate the performance of thetarget controlled infusion（TCI）system with Marsh and Schnider model.3. During TCI,the blood samples in Marsh and Schnider group were analysed bySPSS19.0software to evaluate the performance of TCI system of propofol viacalculating the TCI system bias,precision and wobble.4.Using Nonlinear Mixed Effects Model （NONMEM） to analysis datas of plasmaconcentration under TCI system in gynaecological patients,quantitativelyinvestigating the influence to PPK parameter under the random effects and fixedeffects.The performance of final model was assessed by Plot,Bootstrap,Visual Predicted Check and Normalized Prediction Distribution Error.Result1.Determination of propofol concentrations in human plasma using the HPLC-UVmethod. Calibration curve was=0.453x-0.0497（r=0.9991, n=7）, linear rangewas covered0.1～40μg·mL-1,recovery rate of propofol was99.80%～100.02%withRSD less than1%,the RSD of intra-day and inter-day assays were all less than5%,sensitivity was0.05μg·mL-1（S/N≥3）,endogenous substances in the blood andconcomitant medications did not interfere with the determination.2.Conform to the collection standards,each of40gynaecological patients were inMarsh and Schnider group.The difference of measured and predicted concentrationsin Marsh and Schnider group were not significant （P>0.05） during TCI,while thatwere significant （P<0.05）after TCI.The difference of measured and predictedconcentrations in Marsh group was closing to0.3.The bias MDPE of Marsh and Schnider parameter model were9.90%and14.00%,the precision MDAPE of them were11.43%and14.49%,the wobbleMDADPE of them were7.77%and7.79%.4. Analysis1379datas of plasma concentration under TCI system in93gynaecological patients by Nonlinear Mixed Effects Model.The PPK model ofpropofol could be described as three-compartment model,its pharmacokineticparameters on CL,Q2and Q3are110（WT/56.39）0.54L·h-1,269L·h-1and54.9L·h-1,V1,V2and V3are6.08L,9.32L and50.2L.Patients,weight could effect CL.The plotsshowed the final model predicted concentrations were evenly distributedsymmetrically around the moving average,the predictive value of most of theconcentration of the blood sample point weights residuals between±2.Bootstrapvalidation showed878runs were successful among1000bootstraps, approximately95%of data fitted well within the2.5th-97.5th percentile.Visual Predictive Check（VPC） showed640out of673points fall inside the95%prediction interval.Normaldistribution prediction error （NPDE） showed that the homogeneity of variance （P>0.05） and according with normal distribution. Conclusion1.The HPLC-UV method is esay,accurate and fast to determine the plasmaconcentration of propofol.2.The precisions of the TCI system inserted Marsh and Schnider parameters areacceptable for clinical use. The predictive ability of Marsh parameter model is muchmore accurate than that of Schnider parameter model.3.Founding the three-compartment model of PPK of propofol for gynecologicalpatients,which is stable and effective.Combining Patients,weight, we can estimate theCL of propofol so as to offer an individual dosage regimen for clinical anesthesia. |
PDF Full Text Request