Cytochrome P450 2D6 Genotype and Methadone Steady-State Concentrations

Abstract

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

Voriconazole drastically increases exposure to oral oxycodone

“…Polymorphism of CYP2D6 has been shown to influence the metabolism of several opioid substrates of CYP2D6 such as codeine [33], tramadol [34] and methadone [35]. Genetic alterations in CYP2D6 enzyme activity have also been suggested to influence the pharmacokinetic profile [36] and clinical effects [37][38][39] of oxycodone.…”

Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

“…Methadone is reported to be metabolized by multiple cytochrome P450 enzymes, including possibly 3A4, 2D6, 2C9, 2C19 and 2B6 [5][6][7][8]22]. Nelfinavir is a moderate inhibitor of CYP3A4 and apparent inducer of at least some of the other P450 cytochrome enzymes.…”

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

“…The effect of CYP2D6 alleles resulting in low versus ultrarapid metabolism has been investigated in methadone-maintained subjects. Although the metabolism of methadone is primarily mediated by CYP3A4, the investigators did find a significant decrease in dose-to-weight corrected methadone concentrations in the ultrarapid metabolizers, but this did not appear to influence treatment outcome compared with the low metabolizer group (Eap et al, 2001).…”