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Effect of Venlafaxine versus Fluoxetine on Metabolism of Dextromethorphan, a CYP2D6 Probe
Author(s) -
Amchin Jess,
Ereshefsky Larry,
Zarycranski William,
Taylor Karen,
Albano Dominick,
Klockowski Patricia M.
Publication year - 2001
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700122010159
Subject(s) - fluoxetine , dextromethorphan , cyp2d6 , venlafaxine , dextrorphan , pharmacology , metabolite , pharmacokinetics , discontinuation , active metabolite , venlafaxine hydrochloride , reuptake inhibitor , cyp3a , urine , chemistry , endocrinology , dosing , medicine , metabolism , cytochrome p450 , serotonin , antidepressant , receptor , hippocampus
Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty‐eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady‐state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7,28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2‐fold for venlafaxine and 9.1‐fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1‐fold for venlafaxine and 17.1‐fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine .