摘要
目的建立快速灵敏的液相色谱-串联质谱法,研究纳曲酮-3-O-辛酸酯在兔体内的药动学。方法纳曲酮辛酸酯进入体内后可快速水解为纳曲酮,因此纳曲酮-3-O-辛酸酯在兔体内的药动学参数可基于纳曲酮的血浆样品浓度检测而获得。血浆样品预处理采用甲基叔丁基醚液液萃取方法,以纳洛酮为内标。采用Agilent Zorbax SB-C18(100 mm×2.1 mm,3.5μm)型色谱柱,以甲醇/0.1%甲酸水溶液(50∶50,V/V)作为流动相,流速0.2 mL·min^(-1);正离子多反应监测模式:纳曲酮(m/z 342.2→324.1),内标纳洛酮(m/z 328.1→310.2);选用12只新西兰大耳白兔,分别im给予等摩尔剂量的纳曲酮和纳曲酮-3-O-辛酸酯,于给药前及给药后不同时间点取血,所得的血药浓度数据采用非房室模型计算主要药动学参数。结果血浆内源性物质均不干扰样品峰,建立的LC-MS/MS体内分析测定方法的绝对回收率>76%,线性范围为0.5~100μg·L^(-1)(r^(2)>0.999)。兔im给予纳曲酮1.0 mg·kg^(-1)后纳曲酮的主要药动学参数为:Tmax为(6.7±2.6)min,Cmax为(681±153)μg·L^(-1),T_(1/2)为(40.0±7.5)min,AUC0-t为(25850±4642)μg·min·L^(-1),MRTtn为(43.7±6.1)min。兔im给予等摩尔剂量的纳曲酮辛酸酯1.2 mg·kg^(-1)后,纳曲酮的主要药动学参数为:Tmax为(240.0±120.0)min,Cmax为(61.3±10.6)μg·L^(-1),T_(1/2)为(295.7±133.0)min,AUC0-t为(30650±6775)μg·min·L^(-1),MRTtn为(406.1±5.0)min。结论本研究建立的LC-MS/MS方法灵敏度高,适用于纳曲酮-3-O-辛酸酯的药动学研究。与im等摩尔剂量的纳曲酮相比,纳曲酮-3-O-辛酸酯的达峰时间和半衰期显著延长,达峰浓度显著降低。
OBJECTIVE To develop a rapid and sensitive liquid chromatography-tandem mass spectroscopy method for the pharmacokinetic study of naltrexone-3-O-caprylate in rabbits.METHODS Naltrexone-3-O-caprylate was completely metabolized to naltrexone after administration,therefore,the pharmacokinetic study was carried out based on the naltrexone concentration in plasma after administration of naltrexone and its esterification prodrug.The analyte and internal standard(naloxone)were extracted from plasma samples by methyl-tertiary-butyl ether.The separation was accomplished on an Agilent Zorbax SB-C18 column(100 mm×2.1 mm,3.5μm)with a mobile phase composed of methanol-0.1 FA water(50∶50,V/V)at a flow rate of 0.2 mL·min^(-1).The ion transitions monitored in multiple reaction-monitoring modes were m/z 342.2→324.1 and m/z 328.1→310.2 for the naltrexone and naloxone internal standard,respectively.Twelve rabbits received im administration of either naltrexone or naltrexone-3-O-caprylate.Blood samples were collected before administration and at different time points after administration.The concentration-time data were analyzed with a non-compartmental method.RESULTS All plasma lots were found to be free of interferences with the compounds of interest.The extraction recovery of naltrexone and naltrexone was higher than 76%.The method was sensitive with good linearity(r^(2)>0.999)over the linear range of 0.5×10^(-6)-100×10^(-6) g·L^(-1).The main pharmacokinetic parameters of naltrexone after intramuscular administration of naltrexone(1.0 mg·kg^(-1))were as follows:Tmax(6.7±2.6)min,Cmax(681±153)μg·L^(-1),T_(1/2)(40.0±7.5)min,AUC0-t(25850±4642)μg·min·L^(-1) and MRTtn(43.7±6.1)min.The main pharmacokinetic parameters of naltrexone after intramuscular administration of an equal molar dose of naltrexone-3-O-caprylate(1.2 mg·kg^(-1))were as follows:Tmax(240.0±120.0)min,Cmax(61.3±10.6)μg·L^(-1),T_(1/2)(295.7±133.0)min,AUC0-t(30650±6775)μg·min·L^(-1) and MRTtn(406.1±5.0)min.CONCLUSION The method established is sensitive,specific,and successfully applied to the pharmacokinetic study of naltrexone-3-O-caprylate in rabbits.Compared with intramuscular injection of an equal molar dose of naltrexone hydrochloride,Tmaxand T_(1/2) of naltrexone-3-O-caprylate are significantly increased,while Cmaxis significantly reduced.
作者
王陈
石童
陈学军
张瑞华
李丽琴
WANG Chen;SHI Tong;CHEN Xue-jun;ZHANG Rui-hua;LI Li-qin(State Key Laboratory of NBC Protection for Civilians,Beijing 102205,China)
出处
《中国药理学与毒理学杂志》
CAS
北大核心
2021年第2期102-108,共7页
Chinese Journal of Pharmacology and Toxicology
作者简介
王陈,博士,副研究员,主要从事代谢组学和药代动学研究,E-mail:wangchenpla@163.com;通讯作者:李丽琴,E-mail:liliqinpla@163.com。
