The Performance Evaluation And The Population Pharmacokinetics Research Of Propofol By Target Controlled Infusion System

Objective1. To establish a HPLC-ECD method for determinating of propofol concentrations in human plasma.2. To evaluate the performance of a target controlled infusion (TCI) system of propofol.3. To investigate the population pharmacokinetics (PPK) of propofol administered by TCI in Chinese patients using Nonlinear Mixed Effects Model (NONMEM).Methods1. HPLC-ECD method. Chromatography column: Waters Nova-Pak phenyl (3.9mm×150mm, 4μm); mobile phase: methanol-phosphate buffer (pH2.8) (65: 35, v/v, include 0.02mol·L-1NaCl), flow rate: 0.9mL·min-1; Temperature: 20℃; electric potential: +900mv; Electrochemical detector was used.2. A total of 395 plasma propofol concentrations by TCI obtained from the 47 surgical operation's patients were collected. All samples were determined by HPLC-ECD method. 229 plasma propofol concentrations of the data were analyzed by Microsoft Excel 2000 program.3. The influence of the fixed and the random effects on pharmacokinetics (PK) parameters of propofol by TCI was investigated using NONMEM.Results1. Determination of propofol concentrations in human plasma using the HPLC-ECD method: Calibration curve was ? = 0.2911x - 0.0259 (r = 0.9993, n = 6); Recovery rate of propofol was 98.5%～102.5% with RSD less than 2% (n = 5); The RSD of intra-day and inter-day assays were all less than 3% (n = 5); Linear range was covered 0.1～40μg·mL-1; Sensitivity was 0.04pg·mL-1 (S/N≥3).2. The bias was 16.13, the precision was 19.53, the wobble was 19.87.3. In the final propofol pharmacokinetic parameters, the total body clearance (CL) was 110 L·h-1, the apparent volume of distribution in the central (V1) was 17.4 L, the apparent volume of distribution in the peripheral compartments (V2) was 24 L, and the intercompartmental clearance (Q) was 54.8 L·h-1.Conclusions1. HPLC-ECD method for determinating propofol concentrations in human plasma is simple, accurate and sensitive. It is suitable for PK study.2. The precision of the TCI system of propofol is acceptable for clinical use, but the bias of the TCI system of propofol is not fit for clinical use, and it may be required to be optimized..3. It was found that the sex significantly influences V1 and the age significantly influences Q.4. A PPK model was developed for propofol by TCI in Chinese patients. Validation studies confirmed the internal stability, validity and predictive performance of the model. Clinical application of the model to patient care may permit selection of an appropriate dose to achieve the target propofol concentration, thus enabling the clinical anesthetists to achieve the desired anesthetic effect in patients by TCI with propofol.