Narcotic Antagonists:
`NALTREXONE
`PHARMACOCHEMISTRY
`AND SUSTAINED-RELEASE
`
`PREPARATIONSPREPARATIONS
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service • Alcohol. Drug Abuse • and Mental Health Administration
`
`ALKERMES EXHIBIT 2038
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 14
`
`

`

`Narcotic Antagonists:
`Naltrexone Pharmacochemistry and
`Sustained-Release Preparations
`
`NIDA
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Alcohol, Drug Abuse, and Mental Health Administration
`
`National Institute on Drug Abuse
`Division of Research
`5600 Fishers Lane
`Rockville, Maryland 20657
`
`For sale by the Superintendent of Documents, U.S. Government Printing Office
`Washington, D.C. 20402
`
`Page 2 of 14
`
`

`

`Naltrexone: Research Monograph 28
`R. E. Willette and G. Barnett, eds.
`National Institute on Drug Abuse, 1980
`
`The Clinical Pharmacology
`of Naltrexone:
`Pharmacology and
`Pharmacodynamics
`
`Karl Verebey
`
`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 administra-
`tion, naltrexone was rapidly and completely absorbed. Peak
`levels of naltrexone and its major metabolite 6ß-naltrexol
`were reached 1 hr after the dose. The high 6ß-naltrexol
`plasma concentrations only 1 hr after drug administration
`indicate a rapid biotransformation process, convertin 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 elimi-
`nates the need of stepwise induction at the beginning of
`nal trexone treatment.
`After intravenous administration of 8 mg naltrexone, the plasma
`levels were unexpectedly high for the low dose, ranging between 32
`and 3 ng/ml. The intravenous drug administration eliminated
`direct exposure to hepatic biotransformation; this is the likely
`reason for the higher naltrexone and the significantly lower meta-
`bolite (6ß-naltrexol) plasma levels.
`A rising dose efficacy study from 100 to 800 mg per day provided
`an opportunity for studying naltrexone at much higher than thera-
`
`147
`
`Page 3 of 14
`
`

`

`148
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`peutic doses. No undesirable naltrexone-related side effects were
`observed during the study. Two weeks after the 800 mg/day doses
`were stopped, the plasma was free of naltrexone and its metabo-
`lites, indicating efficient elimination of the drug from the body.
`Based on these human studies, a 100 mg dose of naltrexone pro-
`vided 2 to 3 days protection against 25 mg of intravenous heroin.
`Naltrexone seems to be well tolerated even at doses well above
`those suggested for opiate antagonist therapy. No toxicity or accu-
`mulation of naltrexone and its metabolites was observed in any of
`the studies. The lack of dependence liability and absence of phar-
`macologic or metabolic tolerance during chronic treatment make
`naltrexone a safe and efficacious orally effective opiate antagonist.
`
`INTRODUCTION
`
`(N-cyclopropylmethylnoroxymorphone) was synthe-
`Naltrexone
`sized by Blumberg et al. in 1965 (1). In animal (2) and clinical stud-
`ies (3,4) it demonstrated longer duration of action and greater po-
`tency than its N-allyl congener, naloxone. Naltrexone was also
`orally efficacious at significantly lower doses than naloxone. This is
`important for a drug which is a candidate for the treatment of ex-
`opiate addicts. The initial trials of naltrexone in man indicated
`good efficacy (opiate antagonism), practicality (long time action and
`oral effectiveness) and safety (low doses). In this overview of nal-
`trexone the available data will be combined to examine naltrex-
`one’s opiate receptor blocking activity as it relates to its total bio-
`logical disposition in human subjects.
`
`The Time Course of Action of Opiate Antagonism
`
`The opiate receptor blocking activity of naltrexone was studied
`by challenging it with intravenous heroin injections in four opiate
`ex-addicts (5). Control data of various objective and subjective re-
`sponses to heroin, collected in the absence of naltrexone, in re-
`sponse to a 25 mg heroin injection was considered as 100%. In the
`test period, during naltrexone therapy (100 mg/day), 25 mg heroin
`challenges were performed 24, 48 and 72 hr after the last naltrex-
`one dose. Individual challenges were at least 10 days apart in the
`same patients. The results are shown in figure 1. Averaging both
`the objective and subjective results, 96% of heroin-related re-
`sponses were blocked at 24 hr, 87% at 48 hr and 47% at 72 hr. It is
`apparent from the figure that the blockade seems to hold longer
`and to a greater extent for subjective responses than for objective
`ones. Pooling pupillary miosis and respiratory depression data (ob-
`
`Page 4 of 14
`
`

`

`CLINICAL PHARMACOLOGY OF NALTREXONE
`
`149
`
`jective), the blockade was 89% at 24 hr, 73% at 48 hr, and only
`20% at 72 hr after naltrexone. The blockade for the subjective re-
`sponses was 99% at 24 hr, 92% at 48 hr and a respectable 57% at
`72 hr after naltrexone. The proposed function of naltrexone is to
`block the subjective (or euphorogenic) effects of heroin which, in
`fact, were blocked more efficiently than the objective ones. It
`should be emphasized that 25 mg of heroin is a substantial dose
`and few addicts can obtain such large quantities of heroin routine-
`ly. Thus the duration and magnitude of the blockade seem highly
`effective for most practical situations.
`
`FIGURE 1. The percent objective and subjective responses are shown after 25 mg
`i.v. heroin 24,48 and 72 hr after 100 mg oral naltrexone. The 100% heroin
`responses were determined in the absence of naltrexone. For detailed description of
`the specific tests, see reference 5.
`
`An interesting observation is that pupillary constriction at 72 hr
`is greater than the 100% control heroin effect. It is possible that
`some metabolic N-dealkylation occurs, producing the strong agon-
`
`Page 5 of 14
`
`

`

`150
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`ist, noroxymorphone, for which Martin et al. (3), Resnick et al. (4),
`and Verebey et al. (5) have observed slight agonistic symptoms.
`Cone et al. (6) reported the isolation of small quantities of noroxy-
`morphone in the urine of subjects taking naltrexone. The small
`amount of agonist may act synergistically with heroin to produce
`the higher than control responses.
`
`The Correlation of Narcotic Antagonism With Naltrexone Plasma
`Levels
`
`The mean naltrexone plasma levels of 4 subjects declined very
`slowly from 2.4 ng/ml at 24 hr to 2.0 ng/ml at 48 hr and to 117 ng/
`ml 72 hr after naltrexone (5). The slow exponential decay at this
`period translates into a 96-hr terminal half-life and a correlation
`coefficient with the total (objective and subjective) heroin-related
`responses of r=0.90. The strong correlation indicates that differing
`individual biotransformation rates may influence the time action of
`naltrexone. Shorter opiate antagonist effects would be expected in
`rapid metabolizers than in slow metabolizers of naltrexone. In fact,
`the shorter ß-phase half-life values of individuals correlated with
`greater responses to heroin at 72 hr after naltrexone (r=0.99). Cor-
`relation was also excellent between opiate antagonism and the
`combined levels of 6ß-naltrexol and 2-hydroxy-3-methoxy-6ß-nal-
`trexol (HMN) of r=0.82 (5). While opiate antagonist potencies of
`these metabolites have been shown to be considerably weaker than
`naltrexone in animals (7,8), there is no data in humans. Based on
`our observations, it appears that naltrexone itself is responsible for
`the major part of opiate antagonism, while the less active metabo-
`lites, which are present in large concentrations in the body, also
`contribute to the opiate receptor blocking activity.
`
`Absorption and Distribution
`
`After oral administration, naltrexone was rapidly absorbed, as
`indicated by the early peaking (1 hr) of naltrexone and 6ß-naltrexol
`in the plasma (5). Complete absorption was confirmed by the find-
`ing that free naltrexone in the 24-hr feces was only 0.3% of the ad-
`ministered dose during chronic administration of 100 mg oral doses
`of naltrexone (5). The low plasma levels of naltrexone indicate that
`a large percentage of the dose is rapidly metabolized and the re-
`maining drug is distributed mainly intracellularly, resulting in the
`presence of a small fraction of the dose in the systemic circulation
`(table 1). Individual variation in the plasma levels of naltrexone
`was greatest during the first 8 hours, suggesting that absorption
`
`Page 6 of 14
`
`

`

`CLINICAL PHARMACOLOGY OF NALTREXONE
`
`151
`
`TABLE 1. Plasma Concentration of Naltrexone
`
`Subjects (n)
`
`Dose
`
`Route
`
`(4)
`* Postaddicts
`* Postaddicts
`(4)
`** Normal volunteers (10)
`** Normal volunteers (9)
`** Schizophrenic patients (8)
`*** Schizophrenic patients (6)
`*** Schizophrenic patients (6)
`*** Schizophrenic patients (6)
`*** Schizophrenic patients (5)
`*** Schizophrenic patients (4)
`**** Normal volunteer (2)
`
`mg
`100 P.O. (chronic)
`100 P.O. (chronic)
`50 P.O. (acute)
`100 P.O. (chronic)
`2 x 200 P.O. (chronic)
`100 P.O. (chronic)
`2 x 100 P.O. (chronic)
`2 x 200 P.O. (chronic)
`2 x 300 P.O. (chronic)
`2 x 400 P.O. (chronic)
`8
`I.V. (acute)
`
`Hours after naltrexone
`2
`4
`8
`12
`
`1
`
`24
`
`(ng/ml)
`2
`4
`8
`20
`36
`44
`46 32 19 10 6 3
`22
`12
`5
`3
`27
`17
`8
`6
`
`9
`2
`3
`5
`6
`9
`
`11
`
`8
`
`3
`
`* Data from reference 5
`** Courtesy of Dr. Jan Volavka, Dept. of Psychiatry, University of Missouri
`*** Courtesy of Drs. N. Klein and G. Simpson, The Rockland Research Institute
`**** Courtesy of Dr. Theodore Smith, Dept. of Anesthesiology, University of Pennsylvania
`
`and distribution rates were the most important individual varia-
`bles (5).
`
`Plasma Levels of Naltrexone and Metabolites
`Substantial individual variation of peak naltrexone levels was
`observed, ranging from 15 to 64 ng/ml 1 hr after 100 mg oral doses.
`After the same dose and time the combined 6ß-naltrexol and HMN
`plasma levels ranged from 83 to 288 ng/ml (5). Table 1 shows the
`plasma levels of naltrexone in different subjects after various doses
`and routes of administration. Irrespective of the size of the dose,
`the plasma levels declined to low levels (2 to 9 ng/ml) by 12 to 24
`hrs after drug administration, indicating extensive metabolism and
`effective distribution of naltrexone. The metabolite plasma levels of
`6ß-naltrexol and HMN were 35- and 12-fold higher than naltrex-
`one, respectively (figure 2). With increasing doses from 100 mg to
`800 mg naltrexone/day the 24-hr plasma levels of naltrexone, as
`well as its metabolites, increased. At the 800 mg/day dose, average
`levels reached were 9 ng/ml naltrexone, 123 ng/ml HMN, and 331
`ng/ml 6ß-naltrexol. Two weeks after discontinuation of medication
`the plasma was free of naltrexone and its metabolites, confirming
`the early observations (5) of rapid and efficient elimination of the
`drug from the body (figure 2).
`
`347-877 0 - 81 - 11
`
`Page 7 of 14
`
`

`

`152
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`FIGURE 2. Naltrexone, 6ß-naltrexol and HMN plasma levels were determined just
`prior to each daily dose of naltrexone (24-hr samples). The incremental weekly doses
`are shown at the bottom of the figure. The ordinate scale 6ß-naltrexol (ß-OL) and
`HMN is from 0 to 400 ng/ml while that of naltrexone is from 0 to 10 ng/ml; (n=6
`from 0 to 6th week; n=5 at 7th week and n=4 at 8th and 9th week). The two
`patients were dropped from the study for medical reasons, not related to naltrexone
`therapy.
`
`Metabolism
`
`The major metabolite of naltrexone in humans is 6ß-naltrexol,
`isolated by Cone in 1973 (9), and the structure was confirmed by
`Chatterjie et al. in 1974 (10). A minor metabolite, 2-hydroxy-3-meth-
`oxy-6ß-naltrexol (HMN), was isolated by Verebey et al. (11) and its
`structure was confirmed using synthesis by Cone et al. (12). The
`
`Page 8 of 14
`
`

`

`CLINICAL PHARMACOLOGY OF NALTREXONE
`
`153
`
`rapid peaking of 6ß-naltrexol just an hour after an oral dose indi-
`cated that immediately after absorption a major portion of naltrex-
`one is biotransformed during its first pass through the liver. HMN
`formation from naltrexone can be postulated through various path-
`ways (11). A logical one is the hydroxylation of 6ß-naltrexol at the
`2 position, followed by methylation at the 3 position. However,
`Cone et al. showed 2-hydroxy-3-methoxynaltrexone in trace
`amounts in the urine of subjects taking naltrexone, opening the
`possibility for the formation of HMN through another route (12).
`
`In an earlier report, Cone and Gorodetzky showed, by gas chro-
`matography and mass spectroscopy, the existence in the urine of
`subjects taking naltrexone of an N-dealkylated metabolite, noroxy-
`morphone, which is a potent agonist (13). This metabolite may be
`responsible for the slight agonistic effects observed in some objec-
`tive and subjective responses following naltrexone administration
`(3,4,5).
`
`Quantitatively, 6ß-naltrexol is the most abundant metabolite
`formed and is excreted both free and conjugated. Naltrexone was
`mostly glucuronidated before excretion and HMN was found only
`in the free form. The trace metabolite, 2-hydroxy-3-methoxynal-
`trexone, was estimated at 0.5% of the administered dose (12). There
`is no estimation at present of the quantity of noroxymorphone in
`human urine after naltrexone administration.
`The opiate antagonistic activity of 6ß-naltrexol varies from
`1/50th to 1/12th of that of naltrexone (7,8) depending upon the spe-
`cies and methods used. Preliminary studies of HMN, using the
`opiate receptor binding assay from rat brain synaptosome prepara-
`tion, indicated that HMN binding to opiate receptors was typically
`antagonist but its affinity was 1000 times less than that of naltrex-
`one (14). If this potency ratio holds in human subjects, HMN may
`not contribute much to the opiate antagonist activity of naltrexone.
`In acute vs. chronic dosing, the 6ß-naltrexol over naltrexone con-
`centration in urine, in the same subjects, may have metabolic im-
`plications (5). The ratio of 6ß-naltrexol over naltrexone remained
`the same (table 2), indicating that naltrexone does not induce its
`own metabolism--a desirable feature for a drug given chronically,
`because the initial stabilization dose remains effective throughout
`the course of the treatment. Based on these studies, the most strik-
`ing effect of biotransformation on the pharmacological action of
`naltrexone is the very high rate of first pass hepatic metabolism of
`the drug.
`
`Page 9 of 14
`
`

`

`154
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`TABLE 2. Concentration Ratio 6ß-Naltrexol/naltrexone in 24-hour
`Urine
`
`Subjects
`
`1
`2
`3
`4
`Mean
`± SD.
`
`Acute
`
`3.4
`3.6
`3.6
`2.7
`3.3
`.4
`
`Chronic
`
`2.5
`4.0
`3.3
`3.4
`3.3
`.6
`
`Naloxone is also biotransformed extensively after oral adminis-
`tration, but into inactive glucuronides. This may be the reason for
`its short time action. Fortunately, the active metabolite formation
`(6ß-naltrexol and perhaps HMN) prolongs the time-action of nal-
`trexone. This occurs in much the same way as formation of active
`metabolites prolongs the time-action of 1- -acetylmethadol, in con-
`trast to methadone, which is converted into inactive metabolites.
`
`Renal and Fecal Excretion of Naltrexone
`Urinary excretion of naltrexone and its metabolites is the major
`pathway of elimination of the drug from the body. The 24-hr recov-
`ery of free and conjugated bases is tabulated in table 3. During
`chronic administration of 100 mg oral doses, 23% naltrexone was
`excreted, mostly conjugated (93%). 6ß-Naltrexol was the major ex-
`cretion product, constituting approximately 66% of the total bases
`in the 24-hr urine, and was excreted 60% free and 40% conjugated.
`HMN was 11% of the bases and was excreted only in the free form
`(5). In the acute study an average of 38% of the dose was recovered
`in the 24-hr urine, compared with 70% in the chronic study (using
`the same subjects). Following an acute dose a certain fraction of
`the drug is distributed into tissue stores; however, after chronic
`dosing the tissues become saturated and a larger fraction of the
`dose is available for renal elimination. This may explain the sig-
`nificantly larger percent recovery of the dose in the chronic study
`(table 3 and ref. 5).
`In earlier studies, the total recovery of the bases, 6 days after a
`50 mg oral dose of naltrexone, was approximately 50% of the dose
`(15). In this study HMN must have been included with 6ß-nal-
`trexol, because it was recently found that the HMN and 6ß-nal-
`trexol PFPA derivatives cannot be separated by gas chromato-
`graphy (16). In another study, after 125 mg oral doses of naltrex-
`
`Page 10 of 14
`
`

`

`CLINICAL PHARMACOLOGY OF NALTREXONE
`
`155
`
`one, 34% of the dose was accounted for from 0 to 24 hr, and 3%
`from 24 to 48 hr (17). The low recoveries in the early studies may
`have resulted from methodological difficulties. In a recent study,
`HMN excretion was quantitated for 5 days after a single 50 mg
`naltrexone dose (12). The recovery of HMN was 4.6% of the admin-
`istered dose, which is compatible to the 3.5% reported in another
`acute study (table 3). Furthermore, there is evidence for the exist-
`ence of 2-hydroxy-3-methoxynaltrexone. This minor metabolite was
`estimated at approximately 0.5% of the administered dose (12).
`Table 4 presents data on the fecal excretion of naltrexone and its
`metabolites. In the chronic study a total of 3.6% of the adminis-
`tered dose was excreted in the feces, mostly as 6ß-naltrexol (80%).
`Both HMN and naltrexone were present in much lower concentra-
`tions, 12 and 8% respectively (table 4 and ref. 5). The data clearly
`indicate that fecal excretion is not an important pathway of elimi-
`nation of naltrexone in human subjects. Collectively, the urinary
`and fecal excretion of naltrexone accounted for 73.6% of the ad-
`ministered dose following chronic drug administration. The missing
`26.4% may be various metabolic intermediates described in the
`pathway to the formation of HMN and other not yet identified me-
`tabolites (11). In healthy individuals no problem of naltrexone accu-
`mulation is predicted during chronic naltrexone use. Since the
`drug is largely dependent on hepatic biotransformation and renal
`
`TABLE 3. Urinary Excretion of Naltrexone and Metabolites,
`24-hr Collection
`(% of Dose Excreted)
`
`naltrexone
`Free
`Bound
`
`6ß-naltrexol
`Free
`Bound
`
`2-hydroxy-3-methoxy
`6ß-naltrexol
`Free
`
`Acute
`Chronic
`
`1.0
`1.1
`
`7.2
`15.0
`
`19.1
`29.0
`
`7.1
`17.5
`
`3.5
`7.6
`
`Total
`
`37.9
`70.2
`
`TABLE 4. Fecal Excretion of Naltrexone and Metabolites, 24-hr
`Collection
`(% of Dose Excreted)
`
`naltrexone
`
`6ß-naltrexol
`
`2-hydroxy-3-methoxy
`6ß-naltrexol
`
`Acute
`Chronic
`
`0.13
`0.29
`
`1.9
`2.9
`
`0.08
`0.44
`
`Total
`
`2.1
`3.6
`
`Page 11 of 14
`
`

`

`156
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`elimination, naltrexone disposition should be studied in subjects
`having hepatic and/or renal problems, to evaluate the safety of
`naltrexone in such a population.
`
`CONCLUSION
`
`The data collected during intravenous heroin challenges in the
`absence and presence of naltrexone showed that the subjective
`heroin-related responses were blocked for a longer period of time
`and to a greater extent than were the objective ones. This is a defi-
`nite advantage for the therapeutic purpose of naltrexone; i.e.,
`blocking the euphoric effects of heroin is more important than
`blocking pupillary constriction. The data also showed that narcotic
`antagonism was related to the plasma levels of naltrexone. Individ-
`ual variation in biotransformation rates may therefore influence
`the time course of narcotic blockade. Fortunately, the chronic ad-
`ministration of naltrexone does not induce the microsomal enzyme
`system, and therefore the rate of biotransformation appears to
`remain unchanged from acute to chronic therapy. This suggests
`that the same dose will deliver the same pharmacological effect in
`chronic use. The lowest effective naltrexone plasma level was 2.0
`ng/ml, providing an average of 86.5% blockade of the effects of 25
`mg heroin. Thus, in therapy for effective opiate antagonistic activi-
`ty, plasma levels of 2.0 ng/ml or greater should be maintained.
`Another therapeutic advantage is the rapid attainment of steady
`state of naltrexone in plasma, which is a function of the total bio-
`logical disposition of the drug. Judged from the plasma level data,
`steady state is achieved by the second daily dose of naltrexone.
`This information is useful for the choice of dose and frequency of
`drug administration, especially during the initiation of therapy.
`For simplicity of naltrexone use, our data indicates that no induc-
`tion from lower doses to maintenance dose is necessary. Therapy
`may begin with the maintenance dose.
`Increasing up to 800 mg naltrexone/day, the plasma levels of
`naltrexone and its metabolites also increased to very high levels
`without toxicity or any other undesirable side effects. Two weeks
`after the discontinuation of 800 mg naltrexone doses the plasma
`was free of naltrexone and its metabolites, indicating rapid and ef-
`ficient drug elimination from the body. This study provides evi-
`dence for the high margin of safety of naltrexone even when con-
`siderably higher than effective opiate antagonistic doses are used.
`In brief, nearly 100% blockade of 25 mg intravenous heroin ef-
`fects can be maintained for 48 hr after 100 mg oral dose(s) of nal-
`
`Page 12 of 14
`
`

`

`CLINICAL PHARMACOLOGY OF NALTREXONE
`
`157
`
`trexone. The absence of pharmacologic or metabolic tolerance
`during chronic treatment provides carefree clinical use of naltrex-
`one. Plasma level monitoring can give reliable estimates of the
`degree of opiate antagonism. The pharmacodynamic investigations
`of naltrexone in man found naltrexone a safe and effective opiate
`antagonist for the rehabilitation of well-motivated narcotic addicts.
`Used with adequate psychological and social counseling, this che-
`motherapeutic modality should be most promising.
`
`REFERENCES
`
`1. H. Blumberg, I.J. Pachter, and Z. Matossiank. U.S. Patent 3,332,950 (July 25,
`1967).
`2. H. Blumberg and H.B. Dayton. Naloxone and related compounds. In H.W. Koster-
`litz, H.O.J. Collier and J.E. Villareal (eds.), Agonist and Antagonist Actions of
`Narcotic Analgesic Drugs, Proceedings of a British Pharmacological Society
`Symposium, Aberdeen, Scotland, July 1971, Macmillan, New York (1973).
`3. W.R. Martin, D.R. Jasinski and P.A. Mansky. Naltrexone, an antagonist for the
`treatment of heroin dependence. Arch. Gen. Psychiat., 28, 784-791 (1973).
`4. R.B. Resnick, J. Volavka, A.M. Freedman and M. Thomas. Studies on EN-1638A
`(naltrexone): A new narcotic antagonist. Am. J. Psychiatry, 131, 648650 (1974).
`5. K. Verebey, J. Volavka, S.J. Mule and R.B. Resnick. Naltrexone: Disposition, me-
`tabolism and effects after acute and chronic dosing. Clin. Pharmacol. Ther., 20,
`315-328 (1976).
`6. E.J. Cone, C.W. Gorodetzky and W.D. Darwin. The identification and measure-
`ment of two new metabolites of naltrexone in human urine. Res. Corn. Chem.
`Pathol. Pharmacol., 20, 413-433 (1978).
`7. K. Verebey, and S. J. Mule. Naltrexone pharmacology, pharmacokinetics and me-
`tabolism: current status. Amer. J. Drug and Alcohol Abuse 2, 357-363 (1975).
`8. H. Blumberg and C. Ikeda. Comparison of naltrexone and ß-naltrexol for narcotic
`antagonist action in rats and mice. Fed. Proc., 35, 469 (1976).
`(N-
`naltrexone
`9. E.J.
`Cone.
`Human
`metabolite
`of
`cyclopropylmethylnoroxymorphonel with a novel C-6 isomorphine configuration.
`Tetrahedron Lett, 23, 2607-2610 (1973).
`10. N. Chatterjie, C.E. Inturrisi, H.B. Dayton and H. Blumberg. Stereospecific syn-
`thesis of the 6ß-Hydroxy metabolites of naltrexone and naloxone. J. Med.
`Chem., 18, 490-492 (1975).
`11. K. Verebey, M.A. Chedekel, S.J. Mule, D. Rosenthal. Isolation and identification
`of a new metabolite of naltrexone in human blood and urine. Res. Comm. Chem.
`Pathol. Pharmacol., 12, 67-84 (1975).
`12. E.J. Cone, C.W. Gorodetzky and W.D. Darwin, F.I. Caroll, J.A. Brine, CD. Welch.
`The identification and measurement of two new metabolites of naltrexone in
`human urine. Res. Comm. Chem. Pathol. Pharmacol., 20, 413-433 (1978).
`13. E.J. Cone and C.W. Gorodetzky. Metabolism of naltrexone and naloxone. Report
`to the Committee on Problems of Drug Dependence. Washington D.C. (1975).
`14. J. Hiller and E. Simon, NYU Medical School, personal communications.
`15. E.J. Cone, C.W. Gorodetzky and S.Y. Yeh. The urinary excretion profile of nal-
`trexone and metabolites in man. Drug Metab. Dispos., 2, 506-512 (1974).
`
`Page 13 of 14
`
`Page 13 of 14
`
`

`

`158
`
`NALTREXONE SUSTAINEDRELEASE PREPARATIONS
`
`16. K. Verebey, A. DePace, D. Jukofsky, J.V. Volavka and S.J. Mule. Quantitative
`determination of 2-hydroxy-3-methoxy-6ß-naltrexol (HMN), naltrexone and 6ß-
`naltrexol in human plasma, red blood cells, saliva and urine by gas liquid chro
`matography. Anal. Toxicol, 4, 33-37 (1980).
`17. H.E. Dayton and C.E. Inturrisi. The urinary excretion profiles of naltrexone in
`man, monkey, rabbit and rat. Drug Metabol. Disp., 4, 474-478 (1976).
`
`ACKNOWLEDGMENTS
`
`The author wishes to thank the following collaborators for pro-
`viding biological samples for analysis: Drs. Nathan Klein and
`George Simpson of the Rockland Research Institute; Dr. Jan V. Vo-
`lavka; The Missouri Institute of Psychiatry; and Dr. Theodore
`Smith, Department of Anesthesiology, University of Pennsylvania
`School of Medicine. The expert technical assistance of Dennis Ju-
`kofsky and Ann DePace and the professional assistance of Drs.
`M.J. Kogan and S.J. Mule are acknowledged with appreciation.
`
`AUTHOR
`
`Karl Verebey
`Director of Clinical Pharmacology and Associate Professor of
`Clinical Psychiatry
`SUNY Down State School of Medicine
`New York State Division of Substance Abuse Services
`Testing and Research Laboratory
`Brooklyn, NY 11217
`
`Page 14 of 14
`
`