Clinical Pharmacokinetics Of Midazolam

OBJECTIVE:To investigate the clinical pharmacokinetic profile of midazolam in Chinese under general anesthesia with intravenous infusion of midazolam.METHODS:1. To establish a sensitive and rapid method for determination of midazoalm in human plasma (serum)by high-performance liquid chromatography (HPLC) with ultraviolet(UV) detection : human plasma, with the internal standards (diazopam) was extracted into hexane : methylene chloride :propanol (64:33:3) following be added NaOH and was separated on Agilent XDB-C18(4.6mm×250mm,5μm)with a mobile phase of water(containing 0.02mol/L NaH₂PO₄)- acetonitrile (52:48)(including 0.02% triethylamine) at a flow rate of 1.0ml/min and detected at 223nm. 2. Clinical pharmacokinetics of midazolam: fourteen patients under general anesthesia with midazolam. The patients were received midazolam by constant-rate infusion of 10-20μg·kg^-1·min^-1 for 20 min respectively. Radial artery blood samples of 3ml were obtained before the infusion and at 1,3,5,7,10,15,20 min after the infusion commence and samples were again collected at 5,15,30,45,60 min and then at 2,4,6,12,18,24 h after the midazolam infusion was discontinued. Plasma midazolam concentrations were determined by HPLC with UV detection. Pharmacokinetic analysis was performed using DAS2.1.1 program. 3.Take the pharmacokinetic parameter to simulate anesthesia by XLMEM system, and then take the result to compare with Maitres' and Katayouns' parameter results. 4. Evaluations studie: nine ASAⅠ～Ⅱpatients received anesthesia with midazolam by microcomputer control infusion pump. The program was imbedded the clinical pharmacokinetic parameters of midazolam. Plasma midazolam concentrations were determined by high performance liquid chromatography with ultraviolet detection. Prediction error(PE) and absolute prediction error(absPE), constancy error(CE) and absolute constancy error(absCE), median performance error(MDPE) and the median absolute performance error(MDAPE), median constancy error(MDCE) and the median absolute constancy error(MDACE) of midazolam samples were caculated.RESULTS:1. Calibration curve for midazolam in detection was linear in the ranger of 10.0～1600 ng/ml (r=0.9991). The method recovery was (25ng/ml=103.786±6.167, 400ng/ml= 96.052±6.006,1600ng/ml=98.942±5.647)%.The extraction recovery was (25ng/ml= 82.178±1.578, 400ng/ml=86.050±1.822, 1600ng/ml=86.308±2.804)%. The within-day RSD and between-day RSD were both less than 10% respectively. 2. The pharmacokintics of midazolam were best described by a simple three-compartment mammillary model. Typical pharmacokinetics parameters (midazolam) were t_1/2a=9.5842±3.032975min, t_1/2β=85.3677±24.54408min, t_1/2γ=339.7365±99.77279 min, V₁=0.1821±0.060627L/kg , CL=119.4344±32.31382ml·h^-1·kg^-1, K10(min^-1) =0.0458±0.013278, K12 (min^-1) =0.0863±0.020904, K21(min^-1)= 0.0175±0.004539, K13(min^-1) = 0.0133±0.004437, K31(min^-1)=0.0024±0.000599。t 1/2a,t₁/2β,t 1/2γ,CL were similar to those report in healthy adult volunteers study by other authors and V₁ was less. 3. The quantity is less in early and is larger in later. 4. In evaluations studie: PE and absPE, CE and absCE were -2.3512% and 13.4656%, 0% and 1.3823% respectively. MDPE, MDAPE, MDCE and MDACE were -3.1467%, 13.5920%,0% and 1.1648% respectively. The measured concentrations were linearly correlated with the predicated concentrations(r=0.999).CONCLUSION:1. The method was accuracy, sensitive and specific for the determination of concentration of midazolam in human plasma, in clinical pharmacokinetic study. 2. Pharmacokinetics of midazolam have significant individual difference during the general anesthesia combined with remifentanil. The dosage of midazolam should be prescribed individually. 3.This pharmacokinetic parameter is possible more agree with Chinese. 4. The TCI system imbedded with clinical pharmacokinetic parameters of midazolam has preferable accuracy and constancy when the program was used in anesthesia supplemented with remifentanil.