Effect of terbinafine and voriconazole on the pharmacokinetics of the antidepressant venlafaxine.
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.
Hynninen
V-V
VV
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku University Hospital, Turku, Finland. vilhyn@utu.fi
Olkkola
K T
KT
Bertilsson
L
L
Kurkinen
K
K
Neuvonen
P J
PJ
Laine
K
K
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000009:adverse effects / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003640:Dealkylation; D000069468:Desvenlafaxine Succinate; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D000077291:Terbinafine; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069470:Venlafaxine Hydrochloride; D065819:Voriconazole
D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011743:Pyrimidines; D014230:Triazoles; D000069470:Venlafaxine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D000077291:Terbinafine; D065819:Voriconazole; D000069468:Desvenlafaxine Succinate