Reuning R H, Batra V K, Ludden T M, Jao M Y, Morrison B E, McCarthy D A, Harrigan S E, Ashcraft S B, Sams R A, Bathala M S, Staubus A E, Malspeis L
J Pharm Sci. 1979 Apr;68(4):411-6. doi: 10.1002/jps.2600680405.
This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.
本研究生成了表征先前报道的用于纳曲酮的特定电子捕获气相色谱分析的数据，并将该方法应用于纳曲酮药代动力学的测定。报告了该分析的提取效率，质谱证据表明，纳曲酮在用五氟丙酸酐和碱催化剂进行电子捕获气相色谱衍生化时形成三酯。猴子静脉注射纳曲酮在两个剂量水平下的血浆浓度-时间数据未显示剂量依赖性动力学的证据。对两只狗体内纳曲酮的血浆浓度-时间数据拟合二室开放药代动力学模型，得出总体清除率为51 - 55 ml/min/kg。收集的0 - 24小时尿液中，36%的剂量为纳曲酮缀合物，未变化的纳曲酮含量低于1%。六只猴子静脉注射纳曲酮的血浆浓度-时间数据得出平均终末半衰期为7.8小时，总体清除率为64 ml/min/kg。在狗和猴子中，纳曲酮的总体清除率均大于肝脏血浆或血流。这一发现，连同纳曲酮极低的肾排泄率，表明除肝脏代谢和肾排泄外，还存在其他消除机制。
