Abstract
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.
Publication types
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antidepressive Agents, Second-Generation / adverse effects
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Antidepressive Agents, Second-Generation / pharmacokinetics*
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Area Under Curve
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Biotransformation
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Cross-Over Studies
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Cyclohexanols / adverse effects
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Cyclohexanols / pharmacokinetics*
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Cytochrome P-450 CYP2D6 / genetics
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Cytochrome P-450 CYP2D6 / metabolism
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Cytochrome P-450 CYP2D6 Inhibitors*
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Dealkylation
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Desvenlafaxine Succinate
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Drug Interactions
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Genotype
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Half-Life
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Humans
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Male
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Naphthalenes / adverse effects
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Naphthalenes / pharmacokinetics
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Naphthalenes / pharmacology*
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Phenotype
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Polymorphism, Genetic
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Pyrimidines / adverse effects
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Reference Values
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Terbinafine
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Triazoles / adverse effects
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Triazoles / pharmacokinetics
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Triazoles / pharmacology*
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Venlafaxine Hydrochloride
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Voriconazole
Substances
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Antidepressive Agents, Second-Generation
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Cyclohexanols
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Cytochrome P-450 CYP2D6 Inhibitors
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Enzyme Inhibitors
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Naphthalenes
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Pyrimidines
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Triazoles
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Venlafaxine Hydrochloride
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Cytochrome P-450 CYP2D6
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Terbinafine
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Voriconazole
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Desvenlafaxine Succinate