Effect of Terbinafine and Voriconazole on the Pharmacokinetics of the Antidepressant Venlafaxine
Comment from Jessica Oesterheld, M.D.: Although not reported before based on a clinical study, this significant drug interaction is entirely predictable since it is known that terbinafine is a potent inhibitor of CYP2D6 and venlafaxine's major metabolic pathway is CYP2D6. Venlafaxine's adverse effects are known to include increased blood pressure at higher doses as well as Effexor's increased risk of fatal overdoses when compared to other antidepressants.
Mol Ther. 2008 Feb;83(2):342-348. Epub 2007 Aug 8.
Effect of Terbinafine and Voriconazole on the Pharmacokinetics of the Antidepressant Venlafaxine.
Hynninen VV, Olkkola K, Bertilsson L, Kurkinen K, Neuvonen P, Laine K.
 1Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku University Hospital, Turku, Finland  2Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, Turku, Finland.
This study investigated the effect of terbinafine and voriconazole on the pharmacokinetics of venlafaxine in healthy volunteers. Plasma concentrations of venlafaxine and O- desmethylvenlafaxine (ODV) were measured after ingestion of 75 mg venlafaxine without pretreatment (control), after terbinafine pretreatment, or after voriconazole pretreatment. During the terbinafine phase, the area under the plasma concentration-time curve
(AUC((0-infinity))) of venlafaxine was on average 490% (P<0.001) and that of ODV 57% (P<0.001) of the corresponding control value. Terbinafine decreased the AUC((0-infinity)) ratio of ODV over venlafaxine by 82% (P<0.001). Voriconazole slightly increased the sum of AUC((0-infinity)) of venlafaxine plus AUC((0-infinity)) of ODV (active moiety) by 31% (P<0.001). The most likely mechanism for the interaction between terbinafine and venlafaxine is the inhibition of CYP2D6-mediated O-demethylation of venlafaxine, whereas the minor effects of voriconazole are probably due to the inhibition of CYP3A4-, CYP2C9-, or CYP2C19-mediated metabolism of venlafaxine. Clinical Pharmacology & Therapeutics (2008) doi: 10.1038/sj.clpt.6100311.
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