INVOLVEMENT OF CYP3A4, CYP2C8, AND CYP2D6 IN THE METABOLISM OF (R)- AND (S)-METHADONE IN VITRO

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:To clarify the oxidative metabolism of methadone (R)-and (S)-enantiomers, the depletion of parent (R)-and (S)-methadone and the formation of racemic 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were studied using human liver microsomes and recombinant cytochrome P450 enzymes. Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP3A4 was the predominant enzyme involved in the metabolism of (R)-methadone. However, it has different stereoselectivity toward (R)-and (S)-methadone. In recombinant CYP3A4, the metabolic clearance of (R)-methadone was about 4-fold higher than that of (S)-methadone. CYP2C8 is also involved in the metabolism of methadone, but its contribution to the metabolism of (R)-methadone was smaller than that of CYP3A4. But for the metabolism of (S)-methadone, the roles of CYP2C8 and CYP3A4 appeared equal. Although CYP2D6 is involved in the metabolism of (R)-and (S)-methadone, its role was smaller compared with CYP3A4 and CYP2C8. Using clinically relevant concentrations of ketoconazole (1 M, selective CYP3A4 inhibitor), trimethoprim (100 M, selective CYP2C8 inhibitor), and paroxetine (5 M, potent CYP2D6 inhibitor), these inhibitors decreased the hepatic metabolism of (R)-[(S)-]methadone by 69% (47%), 22% (51%), and 41% (77%), respectively. However, inhibition of the metabolism of (R)-and (S)-methadone by paroxetine was due to inhibition not only of CYP2D6, but also CYP3A4 and, to a minor extent, CYP2C8. The present in vitro findings indicated that CYP3A4, CYP2C8, and CYP2D6 are all involved in the stereoselective metabolism of methadone (R)-and (S)-enantiomers. These data suggest that coadministration of inhibitors of CYP3A4 and CYP2C8 may produce clinically significant drug-drug interactions with methadone.

High Frequency of CYP3A4*1B among Opiate Dependent Patients in Malaysia

“…In our previous study in 52 Malay male subjects given a single 8 mg dose of methadone, we found a wide variability in its clearance, consistent with other studies previously reported [28]. The variability in our 52 subjects could not be explained by polymorphisms at the CYP2D6 locus, a very polymorphic gene in our population [19][20][21], another enzyme implicated in methadone metabolism [29]. This led us to investigate the genetic polymorphism at the CYP3A4 locus among heroin drug users.…”

Methadone Induces the Expression of Hepatic Drug-Metabolizing Enzymes through the Activation of Pregnane X Receptor and Constitutive Androstane Receptor

“…Some controversy exists in the literature regarding which cytochrome P450 (P450) isoform(s) plays the primary role in hepatic metabolism and clearance of MD. In previous studies, the predominant mediator of MD metabolism was thought to be CYP3A4, and numerous in vitro and in vivo studies have shown CYP3A4 involvement in the metabolism of MD in human liver or intestines (Wang and DeVane, 2003;Gerber et al, 2004;Kharasch et al, 2004). However, recent studies suggest that CYP2B6 is also involved in the metabolism of MD and may possess a higher affinity for MD metabolism compared with that of CYP3A4 (Gerber et al, 2004;Kharasch et al, 2008;Weschules et al, 2008).…”

Investigation of the Interactions between Methadone and Elvitegravir-Cobicistat in Subjects Receiving Chronic Methadone Maintenance

“…Kharasch and colleagues recently demonstrated that CYP2B6 is of greater importance in the metabolism of methadone than CYP3A4 (17). Methadone undergoes oxidative metabolism to inactive metabolites by several other cytochrome P450 variants, including CYP2C19, CYP2D6, and CYP2C8 (11)(12)(13)(14)(15)(16)(17). COBI is not an inhibitor of CYP2B6; however, it is a moderate inhibitor of CYP2D6 (22).…”

“…Methadone is administered as a racemic of R and S enantiomers, with the R enantiomer having the greater potency at the mu-opioid receptor (10). Methadone undergoes oxidative metabolism to inactive metabolites by several cytochromes, including cytochrome P450 2B6 (CYP2B6), CYP3A4, CYP2C19, CYP2D6, and CYP2C8 (11)(12)(13)(14)(15)(16)(17). Substantial interindividual variation exists (18,19); therefore, changes in methadone plasma concentrations do not necessarily predict the pharmacodynamic response.…”