“Involvement Of CYP3A4, CYP2C8, And CYP2D6 In The Metabolism Of (R)- And (S)-Methadone In Vitro”, 2003-06-01 (; backlinks; similar):
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-diphe-nylpyrolidine 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× 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 μM, selective CYP3A4 inhibitor), trimethoprim (100 μM, selective CYP2C8 inhibitor), and paroxetine (5 μM, 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)-methadone 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.