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Pharmacological Research 50 (2004) 551–559

Methadone—metabolism, pharmacokinetics and interactions
Anna Ferrari∗ , Ciro Pio Rosario Coccia, Alfio Bertolini, Emilio Sternieri
Section of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Policlinico, Largo del Pozzo, 71-41100 Modena, Italy Accepted 4 May 2004

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. © 2004 Elsevier Ltd. All rights reserved.
Keywords: Methadone; Drug–drug interactions; Pharmacokinetic; CYP3A4; CYP2D6

1. 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
∗ Corresponding

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]. 2. Pharmacokinetics of methadone The available methadone hydrochloride on the market is a racemic mixture of two stereoisomers. l-Methadone is the pharmacologically active isomer [5–7] (however, d-methadone retains certain pharmacological effects; for example, the antitussive activity.) Methadone taken orally is

author. Tel.: +39 59 4224064; fax: +39 59 4224069. E-mail address: annaf@unimore.it (A. Ferrari).

1043-6618/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2004.05.002