Cytochrome P450 2D6 genotype and methadone steady-state concentrations

A genetic polymorphism of cytochrome P450 2D6 has been described with the e xistence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The a uthors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients recei ving methadone maintenance treatment (MMT) and genotyped them for cytochrom e P4502D6. The patients' medical records were reviewed to assess the outcom e of the MMT with regard to the absence of illicit opiate consumption and t o 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 rati os. For (R)-methadone, a significant difference was found between ultrarapi d 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. Th ese results confirm the involvement of cytochrome P450 2D6 in methadone met abolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) o f the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolize rs were considered successful in their treatment. More studies are needed t o examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.