Plasma Naltrexone Kinetics after Intravenous Bolus Administration in Dogs and Monkeys

• Published in: Journal of pharmaceutical sciences 1979-04, Vol.68 (4), p.411-416
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Animals; Chromatography, Gas; Dogs; dogs and monkeys; electron capture-specific assay for naltrexone; electron-capture GLC assay; Female; GLC; GLC electron capture—specific assay for naltrexone; Haplorhini; Hydrolysis; Injections, Intravenous; Kinetics; Male; Mass Spectrometry; Models, Biological; Naloxone - analogs & derivatives; Naltrexone - administration & dosage; Naltrexone - blood; Naltrexone - urine; Naltrexone-plasma kinetics after intravenous bolus administration; Naltrexone—plasma kinetics after intravenous bolus administration dogs and monkeys, electron-capture GLC assay; Narcotic antagonists-naltrexone; Narcotic antagonists—naltrexone pharmacokinetics after intravenous bolus administration, dogs and monkeys, electron-capture GLC assay; pharmacokinetics after intravenous bolus administration; Pharmacokinetics-naltrexone after intravenous bolus administration; Pharmacokinetics—naltrexone after intravenous bolus administration, dogs and monkeys, electron-capture GLC assay
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600680405

This investigation generated data characterizing 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 51–55ml/min/kg. Urine collected for 0–24hr 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 7.8hr and a total body clearance of 64ml/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.