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AMER. J. DRUG & ALCOHOL ABUSE, 2(34), pp. 357-363 (1975)

Naltrexone Pharmacology, Pharmacokinetics, and Metabolism: Current Status

K. VEREBEY MULE

s. J.

DACC Testing and Research Laboratory Brooklyn, New York 11217

The major chemotherapeutic approaches to the treatment of opiate dependence are: ( 1) substitution maintenance therapy with a long-acting narcotic agonist such as methadone and la-acetylmethadol, and (2) opiate receptor blockade with a narcotic antagonist such as naloxone, cyclazocine, or naltrexone. Methadone maintenance provided definite social advantages over no treatment at all; however, serious problems were also associated with this program. Among these are the appearance of methadone on the street, itself becoming a primary drug of abuse, creating the “methadone addict” and the potentially lethal effects of methadone when even a small 20 to 30 mg dose is taken by a nontolerant person. In recent years substantial efforts have been made to stop takehome medications and to dispense a long-acting narcotic agonist like la-acetylmethadol or a long-acting narcotic antagonists for the treatment of opiate dependence. Naloxone and cyclazocine (antagonists) were initially used. However, the disadvantages of these drugs were soon discovered. Naloxone had a very short time course of action and thus 2 to 3 g were required daily to maintain narcotic blockade for a period of 24 hr. These very large doses caused discomfort to the patients, and the large amounts of naloxone required for maintenance was extremely expensive. Although cyclazocine 357

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was effective in 4 mg/day doses and had a time action of 72 hr in blocking 25 mg of i.v. heroin, it caused, in some subjects, adverse psychotomimetic effects, especially during induction, which were undesirable. Naltrexone (N-cyclopropylmethylnoroxymorphone,EN 1639A) was synthesized by Blumberg et al. [ 11 in 1965. In animal and clinical studies it appeared to have a longer duration of action and greater potency than naloxone, it caused fewer undesirable side effects than cyclazocine, and it was orally efficacious at considerably lower doses than naloxone. Naltrexone has no addiction liability, thus dispensing it to opiate addicts is easier and less dangerous to the population in every respect than methadone or any other narcotic agonist. In this communication naltrexone will be reviewed with reference to its pharmacology and biological disposition in animals and man, and its current clinical role in the therapeutic treatment of opiate dependence. Naltrexone, although an antagonist, was tested for possible narcotic agonist effects in vivo in mice and rats and in vitro in guinea pig ileum preparations. It essentially had no effect in producing analgesia, and no respiratory depression was observed [ 21. Kosterlitz [31 reported the absence of an agonistic effect on guinea pig ileum preparation. The narcotic antagonistic activity of naltrexone was studied in rats following subcutaneous injections of naltrexone to counteract narcosis produced by previously administered oxymorphone. Naltrexone was 40 times as active as nalorphine and twice as active as naloxone [21. Following the administration of a narcotic agonist to mice, the tail is in a vertical position. This phenomenon is referred to as “Straub tail.” Using the Straub tail assay in mice, naltrexone administered subcutaneously was 2 to 3 times as potent as naloxone; however, following oral administration the activity of naltrexone was 8 times that of naloxone [21. In rabbits, naltrexone given intravenously was twice as active as naloxone in antagonizing the respiratory depression induced by oxymorphone [ 21 . In monkeys, the precipitation of the abstinence syndrome with subcutaneously administered naltrexone was achieved at slightly lower doses than with naloxone [4]. In patients dependent on 60 mg morphine/day, naltrexone administered subcutaneously was 17 times more potent than nalorphine in precipitating abstinence [ 5 I . To determine the time course of narcotic antagonism or blockade produced by naltrexone or naloxone, subcutaneous oxymorphone

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challenges were given to naltrexone- and naloxone-treated rats at variable time intervals [6]. Three hours after drug administration, naloxone had no antagonistic effect on an oxymorphone challenge while naltrexone still produced a 50% blockade. Thus, in rats following oral administration, 118 of a naltrexone dose was required to give the same degree of peak blockade (90% at 30 min) as naloxone. The time action course of naltrexone was about 3 times longer than the one achieved by naloxone [61. The time action of naltrexone at 50 mg doses in man was substantially longer than naloxone but shorter than cyclazocine [ 51 . Thus, in animals and man, naltrexone was more potent and had a longer duration of action than both nalorphine and naloxone. To prolong the narcotic antagonistic action of naltrexone, a slow release complex was prepared [ 7 1. Following a 40 mg/kg naltrexone injection intramuscularly to mice, the zinc tennate preparation maintained about 40% narcotic blockade up to 21 days as compared to the HC1 preparation of naltrexone which provided only 1 day of protection. Thus, after toxicological studies of this preparation, the long-term treatment of opiate addicts with single weekly or monthly doses may be possible. The pharmacology and the narcotic antagonistic activity of naltrexone in man was studied by Martin e t al. [8] and Resnick e t al. [9, 101, Although no agonistic effect of naltrexone was observed following the subcutaneous injection of 0.01 to 80 mg in most patients, a few subjects reported definite agonistic symptoms. The authors suggest that active biotransformation product(s) of naltrexone may produce a slight agonistic effect. The physiologic changes and subjective responses were investigated following a 30-mg oral dose of naltrexone. The results indicate that naltrexone produced only slight changes as an agonist. Thus, compared to a placebo, the systolic and diastolic blood pressure on the average increased (the increase of diastolic blood pressure was statistically significant), the pupils were slightly miotic, the temperature dropped slightly, respiratory rate decreased a little, opiate signs were absent, but some of the opiate symptoms were present and the liking score by both patients and observers were equal to that of the placebo. When the drugs were administered orally, naltrexone at doses of 30 to 50 mg produced a narcotic blockade equivalent to about 2,500 to 3,000 mg of naloxone [81. The abrupt discontinuation of naltrexone after the chronic administration of a 30 or 50 mg daily dose resulted in no signs and

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symptoms of abstinence. The authors conclude that the lack of agonist activity, greater potency, and longer duration of action presents a definite advantage of naltrexone over naloxone in the management of opiatedependent patients. The time action and narcotic blockade against a heroin challenge at different dose levels were studied by Resnick et al. [9, 101. Ninety-four patients were treated chronically with naltrexone at a dosage level of 20 to 200 mg daily. The degree of narcotic blockade was tested by 25 mg intravenous heroin challenges. In the majority of cases, 120 mg naltrexone taken every 2 days provided 48 hr protection against the agonist effects of 25 mg intravenous heroin. After chronic naltrexone administration, the body temperature was unaffected, the EEG records remained normal, and the breathing rate decreased 0.35 breaths/min. No withdrawal effects were noted after abrupt discontinuation of 60 to 200 mg daily doses of naltrexone [ 91. The isolation and identification of a major urinary biotransformation product in man was reported by Cone in 1973 [ 1 11. The urinary metabolite isolated was formed by bioreduction of the keto group at the C-6 position. Based mainly on chemical reactivity of the C-6 alcohol, the Pconfiguration was ascribed to the metabolite, thus named 0-naltrexol (initially referred to as P-hydroxynaltrexone). In 1974 Chattejie et al. [ 12I provided further justification for the 6-P-hydroxy stereochemical configuration using nuclear magnetic resonance, infrared, and mass spectral data. The P-OH configuration of the human urinary metabolite of naltrexone is of interest, especially because information on the pharmacological activity of related compounds are only available on the a-epimers. A substantial species variation with regard to the formation of the a-or P-epimers of naltrexol was observed. Cone et al. [ 131 reported that the urinary metabolite of naltrexone in the dog was mostly conjugated naltrexone, in the rat the studies were inconclusive; while in the guinea pig substantial quantities of free and conjugated 0-naltrexol was produced. Pollock et al. [ 141 found that the chicken produced exclusively the a-epimer and the rabbit the h p i m e r of naltrexol. Pharmacological activity of both epimers of naltrexol in relation to the parent compound was only recently reported [ 151. The rzlative narcotic antagonistic activity was assayed using the jumping response of mice having morphine pellet implantations. Naltrexone was most potent with a pharmacological activity of 1, the a-epimer of

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naltrexol was 1/37th as active as naltrexone, and the weakest antagonistic activity was produced by P-naltrexol, 1/53rd as active as naltrexone. In the chronic spinal dog following precipitation of abstinence, the potency ratio between naltrexone and P-naltrexol was approximately 1112 to 1/15 [ 161. (The potency ratio in humans is unknown.) There should be caution, however, about the interpretation or extrapolation of the potency ratios which may change with different test systems as well as in different species [ 151. The urinary excretion profile of naltrexone as reported by Cone et al. [ 161 have been essentially confirmed by Verebey et al. [ 17, 181 and Inturrisi et al. [ 191. The largest urinary excretion product was free pnaltrexol, 26.3% of the administered dose. The other urinary metabolites expressed as a percent of the administered dose were the following: conjugated P-naltrexol, 16.4; conjugated naltrexone, 9.7; and free naltrexone, 1.2 [ 161. In 6 days following a single 50 mg oral dose of naltrexone, an average of 53.4% of the administered dose was recovered as urinary metabolites. No other routes of excretion nor other metabolites were detected in the above studies. Based on the urinary excretion rate of free naltrexone and free p-naltrexol, the half-life of naltrexone was estimated as 1.1 hr while that of p-naltrexol was 16.8 hr [ 161. The long duration of antagonistic action of naltrexone thus is better correlated with the estimated half-life of the metabolite than that of the parent compound. These preliminary studies indicate that orally administered naltrexone after absorption is rapidly biotransformed into a weaker but substantially longer biologically available antagonist. It should be noted, however, the about 50% of the administered dose is not accounted for, which indicates the pressing requirement for intensive research to elucidate completely the total metabolic and dispositional profile of this therapeutically important narcotic antagonist. ACKNOWLEDGMENT This project was supported in part by NIDA-ADM-45-74-133. REFERENCES [ I ] Blumberg, H., Pachter,I. J., and Matossian,Z.,U.S.Patent 3,332,95O(July 25,1967). [2] Blumberg, H., and Dayton, H. B., Naloxone and related compounds, in Agonist and Antagonist Actions ofNarcotic Analgesic Drugs (H. W . Kosterlitz, H . 0. J. Collier, and J. E. Villarreal, eds.), Proceedings of a British Pharmacological

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Society Symposium, Aberdeen, Scotland, July, 1971, Macmillan, New York, 1973. [3] Kosterlitz, H. W., and Watt, A. J., “Kinetic parameters of narcotic agonists and antagonists,” Reported to the Committee on Problems of Drug Dependence and published in the proceeding of the 30th meeting held in Indianapolis, Indiana, 1968. [4] Villarreal, J. E., and Seevers, M. H., “Evaluation of new compounds for morphinelike physical dependence in the rhesus monkey,” Reported to the Committee on Problems of Drug Dependence and published in the proceedings of the 32nd meeting, addendum 1, held in Washington, D.C., 1970. [5] Martin, W. R., and Jasinski, D. R., Characterization of N-cyclopropylmethyl-7,8dihydro- 14-hydroxynormorphine HCl a narcotic antagonist, clin. phurmacol. Ther. 14: 142 (1973). [6] Blumberg, H., and Dayton, H. B., Naloxone, naltrexone, and related noroxymorphines, in Narcotic Antagonists (M. C. Braude, L. S . Harris, E. L. May, J. P. Smith, and J. E. Villarreal, eds.), (Advances in Biochemical Psychopharmacology, Vol. 8 ) , Raven, New York, 1974. [7] Gray, A. P., and Robinson, D. S., Naltrexone zinc tannate: A prolonged-action narcotic antagonist complex, J. Pharm. Sci. 63: 159-161 (1974). [8] Martin, W. R., Jasinski, D. R., and Mansky, P. A., Naltrexone an antagonist for the treatment of heroin dependence, Arch. Gen. Piychiatry 28:784-791 (1973). [9] Resnick, R., and Volavka, J., Reported to the Committee on Problems of Drug Dependence and published in the proceedings of the 36th meeting held in Mexico City, Mexico, 1974. [ l o ] Resnick, R. B., Volavka, J., Freedman, A. M., and Thomas, M., Studies on EN-1638A (naltrexone): A new narcotic antagonist, Am. J. Psychiatry 131:6 (1974). [ 1 11 Cone, E. J., Human metabolite of naltrexone (N-cyclopropylmethylnoroxymorphone) with a novel C-6 isomorphine configuration, Tetrahedron Lett. 23:2607-2610 (1973). [12] Chatterjie, N., Fujimoto, J. M., Inturrisi, C. E., Roerig, S ., Wang, R. 1. H., Bowen, D. V., Field, F. H., and Clarke, D. D., Isolation and stereochemical identification of a metabolite of naltrexone from human urine, Drug Metab. Disposition 2:401-405 (1974). [13] Cone, E. J., Gorodetzky, C. W., and Yeh, S. Y., Biosynthesis, isolation, and identification of 0-hydroxynaltrexone, Pharmacologist 16:225 (1 974). [ 141 Pollock, S. H., and Fujimoto, J. M., A partial characterization of naloxone and naltrexoned-ketone reductase in rabbit and chicken, Pharmacologist 16:225 (1974). [15] Fujimoto, J. M., Roerig, S., Wang, R. I. H., Chatterjie, N., and Inturrisi, C. E., Roc. SOC.Exp. Biol. Med. 148:443-448 (1975). [16] Cone, E. J., Gorodetsky, C. W., and Yeh, S. Y., The urinary excretion profile of naltrexone and metabolites in man, Drug Metab. Disposition 2:506-5 12 (1974). [17] Verebey, K., Mule!, S. J., and Jukofsky, D., Quantitation of naltrexone in

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human urine using gas-liquid chromatography, Pharmacologist 16:225 (1974). [la] Verebey, K., Mule', S. J., and Jukofsky, D . , Unpublished Observations. [19] Inturrisi, C. E., Personal Communications.

Naltrexone pharmacology, pharmacokinetics, and metabolism: current status.

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