Effect of Venlafaxine versus Fluoxetine on Metabolism of Dextromethorphan, a CYP2D6 Probe

Abstract

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 (Day 0), 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.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…CYP2C9 and CYP2D6 are largely responsible for R-norfluoxetine production (Margolis et al, 2000;Ring et al, 2001). Saturable metabolism and some autophenocopying occurs with chronic dosing (Alfaro et al, 2000;Amchin et al, 2001).…”

Interaksjoner mellom metoprolol og antidepressive legemidler

“…Vi fant ingen studier der man hadde undersøkt i hvilken grad fluoksetin og bupropion interagerer med metoprolol. Men ut fra studier med andre CYP2D6-substrater (12,13), er det all grunn til å tro at også fluoksetin og bupropion vil øke systemisk dose av metoprolol i tilsvarende grad som paroksetin. Dette støttes av to kasusrapporter, der svaert lav hjertefrekvens ble observert ved bruk av metoprolol i kombinasjon med henholdsvis fluoksetin og bupropion (9, 10).…”

“…I andre studier er disse antidepressivene vist ikke å inneha CYP2D6-hemmende egenskaper (12,14). Ut fra dette er det sannsynlig at bruk av venlafaksin, mianserin eller mirtazapin sammen med metoprolol ikke innebaerer noen risiko for klinisk relevante interaksjoner.…”

Co-administration of Fluoxetine Alters the Steady State Pharmacokinetics of Fluconazole after Multiple Oral Administration in Dogs

“…Effects on drugs metabolized by these enzymes can persist for many weeks after fluoxetine discontinuation due to the long half-life of fluoxetine and its active metabolite norfluoxetine [7]. An increased risk of pharmacokinetic drug interactions is the immediate clinical consequence of the inhibitory effects of these drugs on CYP isoenzymes [8,9]. Since both drugs are strong inhibitors to the izoenzyme system, their co-administrations, on a chronic basis, could lead to different types of drug interactions.…”