Venlafaxine and metabolites are very weak inhibitors of human cytochrome P450-3A isoforms

Cytochrome P450-3A isoforms mediate the metabolism of a large number of drugs used in clinical practice (Harvey and Preskom 1996; Ketter et al 1995; yon Moltke et al 1995b). The class of selective serotonin reuptake inhibitor (SSRI) antidepressants has the capacity to inhibit reversibly the activity of human cytochrome P450-3A isoforms, accounting for a number of pharmacokinetic drug interactions. Cotreatment with fluoxetine, for example, impairs metabolic clearance and/or elevates steadystate plasma concentrations of P450-3A substrates such as diazepam, alprazolam, amitriptyline, imipramine, and carbamazepine (Greenblatt et al in press). The inhibitory activity of fluoxetine appears to be attributable mainly to its metabolite, norfluoxetine. Fluvoxamine also is a P450-3A inhibitor, causing pharmacokinetic interactions with alprazolam (Fleishaker and Hulst 1994), diazepam (Perucca et al 1994), and haloperidol (Daniel et al 1994). The antidepressant nefazodone, which produces presynaptic serotonin and norepinephrine reuptake inhibition and postsynaptic serotonin (5-HT) 2 receptor blockade (Ellingrod and Perry 1995), is a reasonably potent 3A inhibitor (von Moltke et al 1996b), significantly elevating plasma concentrations of alprazolam (Greene et al 1995) and triazolam (Barbhaiya et al 1995) when coadministered with these drugs. The antidepressant venlafaxine (VF) acts by blocking reuptake