Pharmacokinetics Of Remifentanil During Target Controlled Infusion

Objetive: To estabilish a method for the determination of remifentanil in human blood by GC-MS-SIM .To calculate the pharmacokinetic parameters of remifentanil undergoing TCI, and to analyze the character of pharmaconetics of remifentanil.Method: fifty ASAⅠorⅡpatients (27 man, 23 woman )undergoing elective operation under general anestesia aged 18-60 years, and the body weight were 45-73kg. All patients without mantal and nervous diseases, without uncontrolled high blood pressure (BP≥160/100mmHg), without using opiums and diazepams. All patients'body mass index, heart, lung, liver, ren and body temperature were in good condition. All patients were premedicated with atropine for 0.5mg. The temperature of operation room was controlled range 22-24℃. NIBP, HR, ECG, Spo2 were monitered after patients entered into the operation room. LR was infused from wein in the arm and inhaled pure oxygen for 3min, target plasma concentration of propofol was set at 2-5μg/ml(TCI pump made by silugao of Beijing, tackley parameters), 5min later remifentanil was infused from another vein in arm, target plasma concentration of remifentanil was set at 3ng/ml(TCI pump made by silugao of Beijing, minto parameters), vecuronium 0.1mg/kg was infused simultaneously, intubation after 3-5min, infusion remifentanil for 10min. Arterial blood samples 1.0ml were taken at 1,2,3,5,7,10,11,12,13,15,17,20min after drug administration, then collected it into the tube containing 20μl 50% citric acid, and freeing at–20℃,recorded the dosage of remifentanil in every blood collecting time. 1.0ml of citrated whole blood, 50μl of fentanyl (2000ng/ml),2.0ml actetonitrile,4.0ml methylene chloride were added to a 15ml polypropylene centrifuge tube. The mixture was vortex-mixed for 60s and centrifuged for 15min at 1000g. The organic phase was transferred to a second 10ml borosilicate glass, screw-top tube evaporated to dryness under a stream of nitrogen at room temperature. The residue was reconstituted in 50μl of acetiamine, and vortex-mixed for 60s and inject into vaporiser. The GC-MS conditions: The GC oven was equilibrated at 130℃immediately prior to injection and for 2.5min post-injection. The oven temperature was initially increased from 130 to 210℃at 50℃/min, and then from 210 to 280℃at 6℃/min with no hold time after either increase. The oven temperature was then ramped from 280 to 320℃at 50℃/min with a 2min hold at 320℃. The injection port was heated at 250℃. The transfer line was heated at 300℃. The flow rate of high pure helium gas(99.999%) was 1ml/min, The sample injected way was splitless injection. The auto-injector was programmed to inject up to 1.0μl of the sample into the programmed temperature vaporiser. the chromatographic column was HP-5MS,30m×0.25mm×0.25μm, fentanyl was as the internal standard, the selected ion monitoring (SIM) mode was used for the determination of remifentanil to obtain the desired sensitivity. The ions selected were m/z 168, 212, 227 for remifentanil and m/z 146, 245 for fentanyl.Result: The standard curver found to be linear at range 0.05-250ng/ml , standard curver :Y=0.05521+0.03025X, good corralation ( r=0.99831 ), the limit quantitation was 0.05ng/ml, recovery of extration was 85.42-94.95%, recovery of method was 92.33-106.55%, RSD was less than 5.2% within-day and RSD was less than 6.1% between-day. The pharmacokinetics profile of remifentanil given by TIC in Chinese was best destribed by two-compartment model. Pharmacokinetic parameters: t1/2α:(1.7±0.4)min t1/2β:(18±9)min k21: 0.12±0.05 k10:0.73±0.14 k12:0.23±0.06 Vd :(40.71±18.23)l Cl: (2.81±0.25)l/min AUC:(37.02±12.15)(ng/ml)min。Conclusion: GC-MS- SIM is the most sensitive method for the determination of remifentanil in human blood in the world till now, it is very suitable for determination the concentration of remifentanil and the study of pharmacokinetics of remifentanil. The pharmacokinetics of remifentanil in Chinese can be best destribed by two-compartment model, the volume distribution in this study is significantly different from that report in foreign studies, indicating there may be some difference in pharmacokinetics of remifentanil between different populations.