Methadone—metabolism, pharmacokinetics and interactions
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
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