Disposition and pharmacokinetics of naltrexone after intravenous and oral administration in rhesus monkeys.

The purposes of this investigation were to determine the disposition of naltrexone (NTX) in monkeys and assess the role of first-pass metabolism and enterohepatic cycling in the disposition process. Concentrations of naltrexone and three metabolites were determined in plasma and urine as a function of time after po and iv NTX administration in six monkeys. Urinary recovery of NTX and metabolites 0-48 hr after iv administration (10 mg/kg) totaled 52% of the dose. Recovery in feces was minimal. Total urinary excretion of NTX and metabolites after po administration was 89% of that after iv administration, suggestive of good absorption of NTX from solution. However, the area under the plasma level-time curve for NTX after po administration was only 3.6% of that after iv administration, indicating a very high first-pass effect. The calculated extraction ratio was 0.96-0.99. Analysis of plasma level-time and urinary excretion rate-time data for NTX, conjugated NTX, beta-naltrexol, and conjugated beta-naltrexol after iv administration revealed that 1) the decline of plasma levels or urinary excretion rates with time for the conjugated metabolites was parallel to the decline for the apparent precursor; 2) the decline of plasma levels or urinary excretion rates for beta-naltrexol was slower than for naltrexone; and 3) there is evidence for a pronounced enterohepatic cycling of conjugated NTX and conjugated beta-naltrexol that influences the plasma level-time profile of these conjugates and the unconjugated compounds as well.

Pharmacokinetic quantitation of naltrexone controlled release from a copolymer delivery system.

Naltrexone release rates from a controlled release delivery system have been quantitated over a time period greater than one month in the monkey. The method requires calibration of the pharmacokinetic parameters of each monkey utilizing an intravenous bolus dose and assay of unchanged naltrexone levels in plasma as a function of time after dosing. Also required are periodic plasma levels of unchanged naltrexone obtained subsequent to administration of the delivery system. Release rates are then calculated as well as the total amount released. Application of the methodology to a biodegradable copolymer naltrexone delivery system in three monkeys showed an initial release rate of 3-8% of the dose per day over the first 3-5 days followed by a slow, rather constant release rate of 1-3% per day from day 5 to the time of the last measurable plasma sample (36-43 days). Comparison of alternative calculation methods using both experimental and simulated plasma naltrexone data verified the accuracy of the release rate calculations. The sum of the calculated total amount of naltrexone released plus the assayed amount remaining in the delivery system after removal from the animal accounted for 91-94% of the administered dose in the two monkeys in which complete data were obtained.

An electron-capture gas chromatographic assay for naltrexone in biological fluids.

The electron-capture gas chromatography assay for naltrexone is an adaptation of the method published originally by Sams and Malspeis (1). The current methodology, described in detail, consists of an extraction procedure, derivatization to form an electron-capturing triester, and gas chromatography using an OV-17 column. Extraction efficiencies indicate that either benzene or 0.25% butanol in cyclohexane used as the organic phase yields maximal extraction of naltrexone and minimal extraction of most naltrexone metabolites. Methylene chloride, on the other hand, yields an optimal combination of clean chromatograms and high extraction efficiencies for both naltrexone and its metabolites. Derivatization with either heptafluorobutyric anhydride or pentafluoropropionic anhydride together with a basic catalyst yields a triester derivative. Use of an OV-17 chromatographic column with electron-capture detection permits assay of naltrexone specifically with respect to known metabolites. One minor metabolite, 2-hydroxy-3-O-methyl-beta-naltrexol could interfere with naltrexone quantitation if present in sufficient quantities. This interference could readily be detected if it were to occur. Data on the reproducibility of this assay procedure indicate that it is sensitive to a concentration of 0.25 ng/ml plasma.

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

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.