VOL.18, N0.1
`SEPTEMBER 1977
`
`Research Communications in
`Chemical Pathology and Pharmacology
`
`ESTIMATION OF THE SYSTEMIC AVAILABILITY AND OTHER PHARMACOKINETIC
`PARAMETERS OF NALTREXONE IN MAN AFTER ACUTE AND CHRONIC ORAL
`ADMINISTRATION
`
`M.J. Kogan, K. Verebey and S.J . Mule
`New York State Office of Drug Abuse Services
`Testing and Research Laboratory
`Brooklyn, New York 11217
`
`Abstract
`First pass metabolism, metabolic clearance, volume of distribu-
`tion and steady state plasma levels were estimated in man fol-
`lowing acute and chronic 100 mg oral doses of naltrexone . Es-
`sentially no statistical difference was observed in these values
`between the acute and chronic physiologic state. The values for
`the first pass effect were 79.6 ± 4.6% and 78.0 ± 3.0% for acute
`and chronic treatment respectively. From our pharmacokinetic
`data an apparent chronic release rate (ACRR) for a sustained re-
`lease preparation of naltrexone was calculated as 11.8 ~g/kg/hr.
`In practice a release rate of one half the ACRR should be suffi-
`cient to provide continuous antagonism of 25 mg i .v. heroin.
`In
`conclusion our data clearly indicate that naltrexone is an ef-
`fective and safe narcotic antagonist in man.
`
`Introduction
`Studies of orally and intravenously administered naloxone to man
`(Fishman, et ~., 1973) and rats (Weinstein, et ~·· 1973) suggested the
`existence of a large first pass metabolism after oral administration.
`More recently, Verebey et !l· (1976) reported urinary, fecal, and plasma
`levels of naltrexone, the N-cyclopropylmethyl congener of naloxone, in
`man after single and multiple 100 mg oral doses of maltrexone. This
`study suggests that the pharmacokinetics of naltrexone in man can be ex-
`plained by a two compartment open model, and that naltrexone was subject
`to a large first pass metabolism as suspected by Cone et ~· (1974) . The
`extent of the first pass effect (1-f) can be estimated by using either
`the blood flow model of Gibaldi et ~· (1971), which assumes virtually
`complete liver metabolism, or by a more generalized form of the blood
`flow model (Vaughan, 1975) which includes both renal excretion and hepa-
`tic metabolism. We chose the latter method because the investigations of
`
`29
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`VOL.18, N0.1
`SEPTEMBER 1977
`
`Research Communications in
`Chemical Pathology and Pharmacology
`
`Verebey et ~· (1976) demonstrated that naltrexone does undergo hepatic
`In this communication we report in ad-
`metabolism and renal excretion.
`dition to the first pass metabolism, the metabolic clearance, the volume
`of distribution and the steady state plasma levels for naltrexone in man
`after acute and chronic administration.
`
`t4ethods
`The clinical study protocol for naltrexone administration, sample
`collection, and analytical techniques were as described previously by
`Verebey et ~· (1976). The total area under the plasma level curve (AUC)
`was estimated using the trapezoidal rule, while that under the terminal
`portion of the curve was the concentration of the last sampl ing time
`(24 hr) divided by the slope of the slow disposition phase (e) (Stramen-
`tinoli et !l·, 1976) . The initial plasma concentration was zero at t=O
`for the acute (single dose) case, while for chronic treatment, the ini-
`tial naltrexone concentration at t=O was taken as the 24 hr concentra-
`tion after the last daily dose. The percentage first pass metabolism was
`calculated from the AUC, as was the metabolic clearance and the apparent
`volume of distribution . The steady state plasma concentration following
`multiple dosing was also calculated. The method of Greenblatt et !L·
`{1976) was employed in calculating the metabolic clearance and the steady-
`state plasma concentration.
`
`Results and Discussion
`In Table I appears the pharmacokinetic data on naltrexone in man af-
`ter acute and chronic oral administration of the drug. Essentially, no
`statistical differences were observed between the acute and chronic phy-
`siologic state for first pass metabolism, metabolic clearance or volume
`distribution. This might be expected since steady state conditions were
`achieved immediately after the first dose . The large magnitude of the
`apparent volumes of distribution suggest that the drug is both intracel-
`lular1y as well as extracellularly distributed.
`Inspection of the Verebey et !l· (1976) data revealed, among other
`things. that:
`
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`-<
`:::J
`OQ
`0 "'
`0 0 -::
`n -·
`~ .a
`3 n
`.. -·
`~ =
`~ 0 = 3 ~3 ::rc:
`-<
`'"'
`OQ :r
`-..
`o n
`~ ~ -"' =-~
`0 ~
`'"' ::r
`
`~
`
`n
`~.
`
`~
`
`-
`
`""C;:IO
`
`c:Dz ;o -- I.D
`
`.......
`.......
`
`~:0
`""""· m .-
`""'=',.-
`Vl< mo
`
`10.9±2.0
`
`12.0
`
`12.9
`
`8.4
`
`Steady State Plasma Levele
`
`10. 1
`Chronic
`iJQ/1
`
`15.0
`
`14.5
`
`14.1
`Chronic
`
`10.8
`
`22.0
`
`18.8
`--
`Acute
`
`70.2
`
`76.6
`
`71.0
`
`84.9
`
`74.2
`Chronic
`
`74.0
`Acute
`
`-
`
`First Pass Metabolismb Metabolic Clearancec Volume of Oistributiond
`
`1/kg
`
`1/hr
`
`74.7
`
`80.9
`
`76.3
`
`85.5
`
`80.1
`Chronic
`
`75.7
`Acute
`(1-f) X 100 (%)
`
`Pharmacokinetics of Naltrexone in Man After Acute and Chronic 100 mg Oral Dosesa
`
`Steady State Plasma Level = AUC6/T, where T = 24 hr.
`e
`Volume of Distribution = f•D/AUC 8.
`d
`area under the curve.
`Metabolic clearance = f·D/AUC, where f is the systemic availability, 0 = the administered dose and AUC =
`c
`Determined by the method of Vaughan, 1975; hepatic blood· flow rate= 1.53 1/min.
`b
`Data from Verebey et al., 1976
`a
`X ± S.D.
`(75.9 kg)
`
`--
`
`16.1 ±5. 2 14.2±0.8
`
`77.0±6.0 73.4±2.7
`
`78.0±3.0
`
`79.6±4.6
`
`13.1
`
`12.6
`
`72.4
`
`78.2
`
`76.2
`
`80.7
`
`R.J.
`
`(69.1 kg)
`
`C.L.
`
`(81.8 kg)
`
`B.P.
`
`{61.3 kg)
`
`E.M.
`
`Subject
`
`Table 1
`
`w -
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`VOL.18, NO.1
`SEPTEMBER 1977
`
`Research Communications in
`Chemical Pathology and Pharmacology
`
`(1) the biologic half-lives t~ (B) of naltrexone was 10.3 hr in the
`(2) a steady state equilibrium
`acute, and 9.7 hr in the chronic case;
`was reached immediately after the first dose; and (3) chronic adminis-
`tration of naltrexone does not result in accumulation of the drug in
`plasma .
`The latter two observations are consistent with the low value of 1.2
`calculated for the accumulation ratio R ={1-e-et)-1 . Accumulation of
`drug was not observed probably because the dosing interval was every two
`ha 1f-1 i ves.
`The magnitude of the renal clearance of naltrexone (10-110 mg/min)
`was such that it had a minimal effect on the calculated first pass effect.
`By omitting the renal clearance term in the Vaughan (1975) model, the
`equation reduces to the one described by Gibaldi et !!., 1971. To illus-
`the mean ± S.D. chronic systemic availability calculated from the
`trate:
`Gibaldi et !l·• 1971 model was 0. 216 ± 0.029, while the Vaughan.(1975)
`model yields 0.220 ± 0.030. Neither model was sensitive to F, the frac-
`In the case of naltrexone, F is unity
`tion of the oral dose absorbed.
`(Verebey et !l·• 1976) . Repeating the calculation using the mean renal
`clearance of 0.06 1/min and apparent clearance (Dose/AUC) of 6.0 1/min at
`F=O.S (50% absorption) yields only a slightly higher first pass effect of
`82.5%
`Verebey and Mule' (1975) in their review of naltrexone pharmacology,
`indicated that a slow sustained release preparation of naltrexone could
`be employed for the long term treatment of opiate addicts. Verebey et
`!l., 1976 reported that in man a 100 mg dose of naltrexone blocks the
`euphoric effects of 25 mg i.v. heroin for 48-72 hours after the last chro-
`nic dose of naltrexone; the time at which the naltrexone plasma level is
`about 1.3 ~g/1. The value of 1.3 ~g/1 is approximately 1/10 the chronic
`steady plasma level. A release rate suitable for such a long term sustained
`vehicle can be readily estimated from data in Table 1. The apparent chro-
`nic release rate (ACRR) is the product of the metabolic clearance times
`the steady state plasma level. By expressing the release rate in tenns
`of the amount of naltrexone (~g) released per kg body weight per hour,
`the ACRR becomes 78.0 1/hr x 10.9 ~g/1 t 72 kg (mean body weight). Thus,
`ACRR = 11.8 ~g/kg/hr
`
`32
`
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`VOL.18, N0.1
`SEPTEMBER 1977
`
`Research Communications in
`Chemical Pathology and Pharmacology
`
`Therefore~ a sustained release preparation of naltrexone with a release
`rate of one half the ACRR (6 vg/kg/hr) should be sufficient to provide a
`continuous antagonism to the agonistic effects of a 25 mg i.v. heroin
`challenge. Harrigan et ~-· 1977 reported that continuous naltrexone in-
`fusion of 1-20 vg/kg/hr produced effective blockade of morphine self-
`administration in the monkey. Based on their animal study, they proposed
`a value of 5 ~g/kg/hr as an effective release rate of naltrexone for a
`human drug delivery system.
`In conclusion, it appears that orally administered naltrexone under-
`goes a large first pass metabolism. It is estimated that only one fourth
`of the administered dose actually reaches the systemic circulation. How-
`ever, the drug that becomes bioavailable appears to have a long duration
`of action as reflected in the effective blockade of heroin challenges for
`more than 48 hours (Verebey et !l·• 1976}. The contribution of the major
`metabolite beta-naltrexol to the pharmacologic effects of the drug can
`not all together be excluded since there is evidence of the metabolite•s
`narcotic antagonistic activity in man (Verebey, et ~-· 1976) and in
`other species (Fujimoto et !l·• 1975). From our pharmacokinetic data a
`release rate of 6 pg/kg/hr is suggested as suitable for a sustained re-
`lease preparation of naltrexone in man.
`
`References
`Cone, E.J., Gorodetzky, C.W. and Yeh, S. {1974). The urinary excretion
`profile of naltrexone and metabolites in man. Drug Metab. Dispos., £.
`500-512.
`Fishman. J., Roffwarg, H. and Hellman, L. (1973}. Disposition of nal-
`oxone-7,8-3H in nonmal and narcotic dependent men. J. Pharmacal. Exp.
`Ther. 187, 575-589.
`Fujimoto, J.M., Roerig, S., Wang, R.I.H., Chatterjie, N. and Inturrisi,
`C.E. (1975). Narcotic antagonistic activity of several metabolites of
`naloxone and naltrexone tested in mice. Proc. Soc. Exp. Biol. Med., 148.
`443-448.
`Influence of first-pass
`Gibaldi, M., Boyes, R.N. and Feldman, S. (1971).
`effect on availability of drugs on oral administration. J. Pharm. Sci . ,
`60' 1338-1340.
`
`33
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`VOL.18, N0.1
`SEPTEMBER 1977
`
`Research Communications in
`Chemical Pathology and Pharmacology
`
`Greenblatt, D.J., Smith, T.W. and Koch-Weser, J. (1976). Bioavailability
`of drugs- digoxin dilemma. Cl in. Phannacokin., l• 36-51.
`Harrigan, M.S. and Downs, D.A. (1977). Blockade of morphine self-adminis-
`tration by continuous naltrexone infusion. Book of Abstracts, National
`Drug Abuse Conference. 1977.
`Stramentinoli , G. and Catto, E. (1976) . Pharmacokinetic studies of s-
`adenosyl-i-methionine (SAMe) in several animal species. Pharmacal. Res.
`Comm., .§_, 211-218.
`Vaughan, D.P. (1975). Estimation of biological availability after oral
`drug administration when the drug is eliminated by urinary excretion and
`metabolism. J. Pharm. Pharmac., £[, 458-461.
`Verebey, K. and Mule•, S.J. (1975). Naltrexone pharmacology, pharmacoki-
`netics, and metabolism: Current status. Amer. J. Drug & Alcohol Abuse,
`~. 357-363.
`Verebey, K., Volavka, J., Mule•, S.J. and Resnick, R.B. (1976). Naltrex-
`one: Dispostion, metabolism, and effects after acute and chronic dosing
`Clin. Pharmacal. Ther., 20, 315-328.
`Weinstein, S.H., Pfeffer, M., Schor, J.M., Franklin, L., Mintz, M. and
`Tutko, E.R. (1973). Absorption and distribution of naloxone in rats af-
`ter oral and intravenous administration. J. Pharm. Sci., 62, 1416-1419.
`
`Copyright C 1977By
`PJD Publications Ltd., Box 966, Westbury, N.Y. 11590
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