Study On Population Pharmaeokineties And Metabolic Enzymes Genetic Polymorphisms Of Propofol

BackgroundPropofol is an intravenous anesthetic commonly used in clinical by TCI. However, the variation of the blood concentrations is large because of the individual variation of different patients’ response to propofol. The rational individual regimen for propofol should be used. PPK model is established, which the factors influencing of the propofol metabolism should be investigated by the OFV. It is an effective meathod to realize the individualized medication.ObjectiveEstablish the PPK model to provide the reference for clinical individualized medication.Method1In vivo study1.1Twenty-two pairents who received propofol TCI in Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical Scohool were enrolled. The target concentration was set at1.0μ.g/mL. Blood samples were obtained at6min and12min from the TCI. Then the target concentrations are set2.0μ.g/mL. Blood samples were obtained at6min and12min from the TCI. The concentrations of propofol in human serum at different time were determinate by the high performance liquid chromatography with fluorescence detection method. The median performance error (MDPE), mean absolute performance error (MDAPE), wobble and divergence were calculated to evaluate the system.1.2Forty-four pairents who received propofol TCI in Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical Scohool were enrolled. The target concentrations was set2.5μ.g/mL. Blood samples were seperated at2min,6min,12min,60min,120min,180min, and2min,6min,30min,60min after the TCI stopped. The concentrations of propofol in human serum at different time were determinate by the high performance liquid chromatography with fluorescence detection method.2In vitro study 2.1Establish human liver microsomes and analysis the metabolic kinetics of enzyme-catalyzed reaction of propofol. Meanwhile the effect of different inhibitors on the propofol concentration would be studied.2.2The genotype frequencies of CYP2B6the44patients were detected by PCR-RFLP.2.3The model was investigated by NONMEM. The influence of the genetic polymorphism to the concentrations of propofol would be evaluated by the OFV.Result1In vivo study1.1The equation was y=0.2911x+0.0211(r2=0.999). The average recovery was more than90%, RSD was less than8%.1.2The MDPE1.0ug/mL in6minutes and12minutes were-53.5%,-47.0%, and2.0ug/mL were-40.0%,-35.0%. The MADPE1.0ug/mL in6minutes and12minutes were53.5%,47.0%, and2.0ug/mL were40.0%,35.0%. The wobble1.0ug/mL in6minutes and12minutes were53.0%,46.5%, and2.0ug/mL were39.6%,34.5%. The divergence1.0ug/mL in6minutes and12minutes were47.5%·h-1,35.0%·h-1, and2.0ug/mL were34.0%·h-1,23.0%·h-1.2In vitro study2.1The parameter fo Vmax, Km and Clint were172.413(μM·mg-1·min-1),777.43(μM·L-1) and0.22(min-1·mg-1·rotein)respectively. In the concentration from100to500μM, the inhibitor of CYP2B6clopidogrel can inhibit the metabolism of propofol significantly. However, the inhibitor of CYP2C9fluconazole and the CYP2C19inhibitor omeprazole had no significant effects on the metabolism of propofol.2.2In the44patients, CYP2B6*1/*1is24(53.3%),*1/*6is18(40.9%),*6/*6is2(4.5%). 2.3The final fitted pharmacokinetic parameters of CL1、 CL2、CL3were1.84、0.95、0.36mL·min-1kg-1respectively,V1、V2、V3were15.2、52.7、203L respectively.Conclusions1The proposed method was simple, accurateand sensitive for determining drug concentration of propofol in plasma.2The target concentrations and actually measured concentrations of target-controlled infusion system for propofol in Chinese people were signaficant differerent. As a result, the PPK parameters for Chinese people should be studied.3Propofol metabolism in liver microsomes reaction process was mainly affected by the role of metabolic enzyme CYP2B6.4The propofol serum concentration was affected by the genetic polymorphisms of CYP2B6. The dosage of propofol in patients with CYP2B6*6allele should be adjusted in different patients by NONMEM.