Elsevier

Pharmacological Research

Volume 50, Issue 6, December 2004, Pages 551-559
Pharmacological Research

Methadone—metabolism, pharmacokinetics and interactions

https://doi.org/10.1016/j.phrs.2004.05.002Get rights and content

Abstract

The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably different concentrations are obtained in different subjects, and the pharmacological effect may be too small in some patients, too strong and prolonged in others. Methadone is mostly metabolised in the liver; the main step consists in the N-demethylation by CYP3A4 to EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), an inactive metabolite. The activity of CYP3A4 varies considerably among individuals, and such variability is the responsible for the large differences in methadone bioavailability. CYP2D6 and probably CYP1A2 are also involved in methadone metabolism. During maintenance treatment with methadone, treatment with other drugs may be necessary due to the frequent comorbidity of drug addicts: psychotropic drugs, antibiotics, anticonvulsants and antiretroviral drugs, which can cause pharmacokinetic interactions. In particular, antiretrovirals, which are CYP3A4 inducers, can decrease the levels of methadone, so causing withdrawal symptoms. Buprenorphine, too, is metabolised by CYP3A4, and may undergo the same interactions as methadone. Since it is impossible to foresee the time-lapse from the administration of another drug to the appearing of withdrawal symptoms, nor how much the daily dose of methadone should be increased in order to prevent them, patients taking combined drug treatments must be carefully monitored. The so far known pharmacokinetic drug–drug interactions of methadone do not have life-threatening consequences for the patients, but they usually cause a decrease of the concentrations and of the effects of the drug, which in turn can cause symptoms of withdrawal and increase the risk of relapse into heroin abuse.

Introduction

Since 1965, the year in which Dole and Nyswander [1] proposed the introduction of methadone as a substitute for heroin, its use has spread progressively also in Italy, in particular for the treatment of drug addicts who cannot remain drug-free in spite of detoxication therapies and attendance in therapeutic communities. Maintenance treatment with methadone, performed with doses adequate to the actual needs of the individual addict, contributes to a drop in mortality, to stopping or reducing heroin use, to decreasing or avoiding relapses and criminal activity, to favouring the finding of a job and improving family and social relationships, to reducing the risk of HIV and hepatitis virus infections [2].

The pharmacological characteristics that support the use of methadone as a replacement in the long term treatment of heroin addiction, a pathological condition that has been defined as a “chronic relapsing disorder” [3], are the high oral bioavailability, the long elimination time that makes a single daily administration possible, the lack of behavioural modifications such as to be detrimental to persons carrying out normal work activities, and the availability of a specific antagonist that can be used in the case of overdose. The most negative kinetic characteristics are the inter-individual variability of absorption and metabolism [4] which make it impossible to anticipate, with acceptable approximation, the relationship between dose, blood concentration, and clinical effect [3].

Section snippets

Pharmacokinetics of methadone

The available methadone hydrochloride on the market is a racemic mixture of two stereoisomers. l-Methadone is the pharmacologically active isomer [5], [6], [7] (however, d-methadone retains certain pharmacological effects; for example, the antitussive activity.) Methadone taken orally is subjected to an important first-pass effect and is detectable in the plasma about 30 min after administration [8]. Its bioavailability varies from 41–76 [9] to 85–95% [10]. Thus, following the administration of

Pharmacological interactions and cytochrome P450 (CYP)

Changes in the metabolism and elimination of methadone are mainly caused by inhibition or induction of cytochrome P450, with a consequent increase or decrease of the amount of drug levels in blood and tissues.

P450 and CYP are synonyms. A CYP enzyme is composed of a protein and of a haeme group (as the prosthetic group). This superfamily is divided into families and subfamilies of enzymes on the bases of their amino acid sequence. Each family has an identity of at least 40% in the amino acid

Methadone metabolism

Methadone is metabolised almost exclusively by the liver [10]. The main biotransformation of the two methadone enantiomers is the N-demethylation [40] by CYP3A4 [41].

CYP3A4 is found in the small intestine and in the liver; therefore, it affects both the intestinal and hepatic metabolism of methadone. This enzyme has no genetic polymorphism, it is inducible, and its activity varies greatly among individuals, from 1 to 30-fold in the liver, from 1 to 11-fold in the gut [42]. The major factor

Interactions of methadone

Methadone maintenance treatment must not be interrupted too early. In fact, its aim is to retain drug addicts on treatment for months or years [2]. During these long periods, treatments with other drugs may become necessary in consideration of the high comorbidity of drug addicts [48], and there may be the risk of drug–drug interactions. The classes of drugs that could be used during methadone maintenance treatment and that could produce drug–drug interactions—of the kinetic type—with

Conclusions

The possibility that clinically important interactions occur when methadone is taken concomitantly with other drugs is substantial. Fortunately, most of such pharmacokinetic interactions are not life-threatening; however, they can have important consequences: precipitation of withdrawal symptoms, relapse in the use of heroin in an attempt to relieve them, thus leaving the maintenance treatment. Physicians must, therefore, carefully follow these patients in order to avoid, or at least to notice

References (92)

  • C.C. Scott et al.

    Pharmacological comparison of the optical isomers of methadone

    J. Pharmacol. Exp. Ther

    (1948)
  • G.D. Olsen et al.

    Clinical effect and pharmacokinetics of racemic methadone and its optical isomers

    Clin. Pharmacol. Ther

    (1977)
  • K. Kristensen et al.

    The mu 1, mu 2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine

    Life Sci

    (1995)
  • C.E. Inturrisi et al.

    Disposition of methadone in man after a single oral dose

    Clin. Pharmacol. Ther

    (1972)
  • U. Meresaar et al.

    Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method

    Eur. J. Clin. Pharmacol

    (1981)
  • M.I. Nilsson et al.

    Clinical pharmacokinetics of methadone

    Acta Anaesthesiol. Scand

    (1982)
  • J.W. de Vos et al.

    Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

    Eur. J. Clin. Pharmacol

    (1995)
  • K. Wolff et al.

    Methadone concentrations in plasma and their relationship to drug dosage

    Clin. Chem

    (1991)
  • K. Verebely et al.

    Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment

    Clin. Pharmacol. Ther

    (1975)
  • E. Anggard et al.

    Pharmacokinetics of methadone during maintenance: pulse labeling with deuterated methadone in the steady-state

    Eur. J. Clin. Pharmacol

    (1979)
  • C.E. Inturrisi et al.

    The levels of methadone in the plasma in methadone maintenance

    Clin. Pharmacol. Ther

    (1972)
  • C.E. Inturrisi et al.

    Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain

    Clin. Pharmacol. Ther

    (1987)
  • N. Loimer et al.

    Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels

    Psychopharmacology (Berl)

    (1991)
  • M.I. Nilsson et al.

    Pharmacokinetics of methadone in methadone maintenance treatment: characterization of therapeutic failures

    Eur. J. Clin. Pharmacol

    (1983)
  • K. Wolff et al.

    Steady-state pharmacokinetics of methadone in opioid addicts

    Eur. J. Clin. Pharmacol

    (1993)
  • V.P. Dole et al.

    Methadone plasma level: sustained by a reservoir of drug in tissue

    Proc. Natl. Acad. Sci. USA

    (1973)
  • C.B. Eap et al.

    Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha l-acid glycoprotein

    Clin. Pharmacol. Ther

    (1990)
  • M.J. Garrido et al.

    Alpha-1 acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome

    J. Clin. Pharmacol. Ther

    (2000)
  • G.D. Olsen

    Methadone binding to human plasma proteins

    Clin. Pharmacol. Ther

    (1973)
  • M.J. Garrido et al.

    Influence of plasma–protein binding on analgesic effect of methadone in rats with spontaneous withdrawal

    J. Pharm. Pharmacol

    (1996)
  • J. Holmstrand et al.

    Methadone maintenance: plasma levels and therapeutic outcome

    Clin. Pharmacol. Ther

    (1978)
  • E. Anggard et al.

    Disposition of methadone in methadone maintenance

    Clin. Pharmacol. Ther

    (1975)
  • W.H. Horns et al.

    Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride

    Clin. Pharmacol. Ther

    (1975)
  • M.I. Nilsson et al.

    Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase

    Eur. J. Clin. Pharmacol

    (1982)
  • M.J. Kreek

    Plasma and urine levels of methadone. Comparison following four medication forms used in chronic maintenance treatment

    N.Y. State J. Med

    (1973)
  • Kreek MJ. Methadone in treatment: physiological and pharmacological issues. Handbook on drug abuse. Washington DC: US...
  • M.I. Nilsson et al.

    Effect of urinary pH on the disposition of methadone in man

    Eur. J. Clin. Pharmacol

    (1982)
  • R.C. Baselt et al.

    Urinary excrection of methadone in man

    Clin. Pharmacol. Ther

    (1972)
  • G.D. Bellward et al.

    Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses

    Clin. Pharmacol. Ther

    (1977)
  • D.W. Nebert et al.

    The P450 superfamily: update on new sequences, gene mapping and recommended nomenclature

    DNA Cell Biol

    (1991)
  • J.H. Lin et al.

    Inhibition and induction of cytochrome P450 and the clinical implications

    Clin. Pharmacokinet

    (1998)
  • M. Shou et al.

    Activaction of CYP 3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site

    Biochemistry

    (1994)
  • K.R. Korzekwa et al.

    Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites

    Biochemistry

    (1998)
  • Anonymous. FDA position on product selection for “narrow therapeutic index” drugs. Am J Health Syst Pharm...
  • D.E. Moody et al.

    The involvement of cytochrome P450 3A4 in the N-demethylation of l-alpha-acetylmethadol (LAAM), norLAAM, and methadone

    Drug Metab. Dispos

    (1997)
  • A.H. Beckett et al.

    The biotransformation of methadone in man: synthesis and identification of a major metabolite

    J. Pharm. Pharmacol

    (1968)
  • Cited by (0)

    View full text