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A method designed to quantitate in vivo naltrexone release rates from sustained-release systems has been applied to the evaluation of seven different naltrexone delivery systems in the monkey. The method consists of two phases: a single intravenous bolus dose quantitation of each monkey's pharmacokinetic parameters coupled with a delivery system study in which plasma naltrexone levels are measured throughout the time period of sustained-release. In vivo release rates and the total amount released are then calculated. It should be noted that these determinations require the analysis of unchanged naltrexone in plasma as the only experimental measurement. Data from injectable naltrexone pamoate microcapsule delivery systems indicate that 1) when these microcapsules are suspended in an aqueous vehicle, a significant part of the dose is released very rapidly, yielding release rate-time data that parallel a non-sustained-release control; 2) this rapid release for the aqueous vehicle is followed by a slow release phase lasting to about 24 days for the subcutaneous route and to about 45 days for the intramuscular route; and 3) when these microcapsules are suspended in an oily vehicle there is no initial rapid release, substantial release rates are obtained for at least 60 days, and an average of 89% of the dose is calculated to have been released. Data from implantable naltrexone delivery systems show that 1) the Alza system most closely approximates a zero-order release rate-time profile; 2) the Battelle system provides a rapid initial release followed by a slowly declining release rate; 3) the Dynatech system is characterized by a more rapid initial release rate of 3-8% of the dose per day over the first 3-5 days followed by a rather constant 1-3% per day to about day 36; and 4) essentially complete recovery of the dose was obtained for the Battelle and Dynatech systems.

In the screening and selection of candidate long-acting narcotic antagonist preparations, careful consideration must be given to the choice of animal evaluation models. A simple, rapid method, using analgesia suppression in the mouse tail-flick test, was chosen for preliminary screening. Suitable candidates were then evaluated by following urinary excretion rates and blood levels in the monkey. Afterwards, the most promising preparations were rigorously tested in their ability to interfere with morphine self-administration in monkeys. Final evaluation involved toxicological studies in injection sites and on the whole animal.

The metabolism and elimination of [15,16-3H2] naltrexone hydrochloride was studied in man following oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and nonconjugated and conjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely in minor quantities. Naltrexone was almost completely absorbed following in the urine and only 5% in the feces. A similar urinary excretion pattern was observed after intravenous administration of naltrexone. In early time periods after oral administration there was a rapid increase in free naltrexone plasma levels up to 1 hr and then gradually declined. A similar pattern was observed for conjugated naltrexone and nonconjugated and conjugated 6 beta-naltrexol. These metabolites were found at levels 4-6 times higher than the parent compound at all times sampled. After intravenous administration, nonconjugated naltrexone plasma levels dropped sharply and continuously. The major metabolites exhibited a pattern closely resembling that found for oral administration. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine. The structure of the latter was rigorously proven by 13C-NMR. No evidence for the presence of noroxymorphone or 3-O-methyl-6 beta-naltrexol could be obtained by gas chromatography-mass spectrometry. The metabolism of naltrexone administered subcutaneously was also determined in two subjects. Larger amounts of 2-hydroxy-3-O-methyl-6 beta-naltrexol were found in plasma than had been present after oral or intravenous administration.

Experimental data on 3H labelled naltrexone obtained from the Research Triangle Institute were analyzed. Both plasma and urine curves were resolved into their exponential components. Mean total clearance of unconjugated naltrexone was 3510 (300) ml/min, and its mean urinary clearance was 76.0 (6.8) ml/min. Fraction of dose excreted through urine was between 55 and 60%. Orally administered drug is completely absorbed into plasma. Plasma curve resulting from intravenous administration contained three exponentials: 1.9 (.5)/min, 0.18 (.07)/min and 0.00106 (.00008)/min. Distribution volumes were 7.6 (.7) liters, 60 (12) liters and 164 (16) liters. After oral administration there were two exponentials: 0.012 (.002/min and 0.00122 (.00009)/min. The faster exponential corresponds to gastrointestinal absorption with a half life of about 1 hour.

Two gas liquid chromatographic methods differing mainly in sensitivity are described for the quantitative determination of naltrexone (NT) and its metabolites in human biofluids. Flame ionization detection of the N,O-bis-(trimethylsilyl) trifluoroacetamide (BSTFA) derivatives provided sufficient separation and sensitivity for quantitative of the bases in urine. However, the thousand times lower levels in serum, red blood cells (RBC) and saliva necessitated the use of more sensitive electron capture detection methods of the pentafluoro derivatives of NT and its metabolites. The 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN) and 6 beta-naltrexol (beta-OL) pentafluoro derivatives had nearly identical gas liquid chromatographic retention times in a number of stationary liquid phases. Thus, their separation had to be achieved prior to chromatography. Differential extraction was based on the different partition characteristics of HMN and 6 beta-naltrexol between aqueous and organic solvents. Applicability of the methods was tested using the biofluids of four subjects taking 2 x 200 mg naltrexone per day chronically. Blood, saliva and urine samples were collected at the same time (prior to drug administration), which was 16 and 24 hours after the doses. In the plasma the relative percentages of the bases were 73.5 beta-OL; 23.1 HMN and 3.4 NT. The same in the urine were 76.6 beta-OL, 14.4 HMN and 9.0 NT. The lipophilic nature of HMN and the hydrophilic property of beta-OL may have influenced their distribution into RBC and saliva. In the RBC 96.1% HMN and only trace amounts of beta-OL distributed and in saliva 92.3% of beta-OL and no HMN was found; the difference in both cases was made up by naltrexone to 100%.

The time-action of opiate antagonist activity of naltrexone was evaluated in detoxified ex-opiate addicts, using 25 mg intravenous heroin challenges. A 100 mg naltrexone dose provided 96% blockade at 24 hr, 86.5% blockade at 48 hr and 46.6% blockade at 72 hr. Following oral administration, naltrexone was rapidly and completely absorbed. Peak levels of naltrexone and its major metabolite 6 beta-naltrexol were reached 1 hr after the dose. The high 6 beta-naltrexol plasma concentrations only 1 hr after drug administration indicate a rapid biotransformation process, converting a large fraction of the dose to less active metabolites. Over 70% of the dose was excreted in the 24 hr urine and less than 0.5% in the feces. No change was observed in the rate of naltrexone disposition during chronic dosing vs. the acute study, indicating no metabolic induction. The rapid achievement of steady state naltrexone plasma levels eliminates the need of stepwise induction at the beginning of naltrexone treatment.