| Background:Nalmefene hydrochloride injection was approval to be used for reversing the adverse reactions such as respiratory depression and low blood pressure that caused by opiates after surgery in 1995 by the United States FDA。It has been clinical applied for 10 years and the clinical efficacy was good. But the drug was not yet used in china.Aim:To study the pharmacokinetic characteristics of Nalmefene hydrochloride that advanced in Pharmaceutical Technology Development Company in Chengdou Bo-Rui and the Military Academy of Medical Sciences Institute of Chinese PLA in healthy volunteers,we established the determination of plasma and urine concentrations of Nalmefene hydrochloride by liquid chromatography - tandem mass spectrometry (LC-MS/MS),and provided scientific basis of reasonable application of the drug for the people.Methods:1 Investigation the best conditions of nalmefene (REVEX) in plasma and urine samples sample preparation and chromatographic separation, and verification. 2 10 healthy volunteers were intravenous injection given 0.5 mg, 1mg, 2mg Nalmefene hydrochloride for single dose in succession. The plasma and urine sample were Collected according to programmed schedule. The electrospray ionization positive selected reaction monitoring detections for Nalmefene hydrochloride and allyln-oroxymorphone ( the internal standard)in the plasma and in the urine were used. the pharmacokinetic parameters and dependability of deference dose were calculated by 3 P87 software .And the same time the adverse were recorded.Result:1 REVEX and NLX was well separated and there was no significant interferential peak .the method exhibited a good linearity in 0.04 to 625ng/ml of REVEX with the lowest detection limit of 0.0008 ng/ml in plasma.The deviation of recovery ratio was found in the range of 92.50%～108.40%.and the standard curve was y = 0.0148x + 0.0055,r=0.9990,n=11.Both RSD between days and within day were all lower than 10%.Meanwhile in the urine samples, a good linearity in the range 0.2 to 625 ng/ml and the lowest detection limit of 0.0003 ng/ml .The limit of the detection for Nalmefene hydrochloride was 0.0003 ng/ml in urine. the standard curve was calculated to be y = 0.0514x - 0.0059,r=0.9999,n=9. The deviation of recovery ratio 90.00%～108.40%. Both RSD between days and within day were all lower than 10%.These results showed the method established in the study is specific for determination of REVEX and could be used in researching drug pharmacokinetics.2 The pharmacokinetics of REVEX were fitted in a two-compartment open model following intravenous administration single dose of 0.5 mg,1mg,2mg of Nalmefene hydrochloride . the obtained pharmacokinetic parameters were as follows respectively:Cmax were (1.74±0.48)ug/L, (4.1 7±1.08)ug/L,(7.88±2.89)ug/L;t1/2βwere (12.83±3.98)h,(12.6±6.4)h,(10.58±3.74)h; V were(3.45±0.16)L/kg,(4.11±0.0716)(L/kg),(4.25±0.56)L/kg; CL were (0.81±0.11)L/hr/kg, (0.85±0.15)L/hr/kg,(0.87±0.11)L/hr/kg;AUC 0-∞were(21.62±9.34) (ng/L)*h,(24.89±8.52)ng/L)*h,(35±11.2)ng/L)*h; there was a significant correlation was observed between the mean peak concentration and AUC0-∞.within 48h ,after an intravenous administration single dose of 0.5 mg,1mg,2mg of Nalmefene hydrochloride . the urine accumulative excretory rate were (78±5.3)%,(71±6.7)%,(78±8.5)% respectively.3 In generally, no serious adverse reactions and significant clinical changes were observed in the period of study. Records of adverse reaction as follows: one volunteer after single intravenous administration of 2.0mg showed a slight lethargy .this symptom was disappeared completely after test without any mediation. and in the laboratory tests a slight rise of Tbil with no clinic significance was found and recovered to normal by themselves.Conclusion:REVEX has good safety. There was no serious adverse reaction in the study.The determination method for Nalmefene hydrochloride in the plasma and in the urine by the electrospray ionization positive selected reaction monitoring detections is exclusive, accurate, sensitive and suitable.Domestic nalmefene hydrochloride injection pharmacokinetic characteristics of 3 groups by intravenous administration in human were described by a two-compartment model. The pharmaceutical characteristics of Nalmefene hydrochloride in human body were linear in the range of 0.5mg-2.0mg. That over 40% of REVEX be excreted in urine within 48h showed it was the main discharge route. |
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