Comparative CYP3A4 Inhibitory Effects of Venlafaxine, Fluoxetine, Sertraline, and Nefazodone in Healthy Volunteers

Abstract

An antidepressant for use in the patient receiving concomitant drug treatment, over-the-counter medications, or herbal products should lack cytochrome P-450 (CYP) 3A4 inductive or inhibitory activity to provide the least likelihood of a drug-drug interaction. This study addresses the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4. In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days. Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken. CYP3A4 activity was evaluated for each subject at baseline and following each antidepressant using the erythromycin breath test (EBT) and by the pharmacokinetics of alprazolam (ALPZ) after 2-mg dose of oral ALPZ. Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism (P > 0.05). For nefazodone, a statistically significant inhibition was observed (P < 0.0005). Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P < 0.05) compared with values at baseline. No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested. These results demonstrate in vivo that, unlike nefazodone, venlafaxine, sertraline, and fluoxetine do not possess significant metabolic inductive or inhibitory effects on CYP3A4.

In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran

“…fda.gov/drugsatfda_docs/nda/2004/021427_s000_Cymbalta.cfm and http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 021427s021s027s028lbl.pdf). In contrast to the situation with duloxetine and several other antidepressants (Bertilsson et al, 2002;Preskorn et al, 2007), genetic polymorphisms in CYP2D6 and CYP2C19 have no impact on the PK of milnacipran (Puozzo et al, 2005) nor does inhibition of CYP2D6 and CYP3A4 by fluoxetine (DeVane et al, 2004;Puozzo et al, 2006). Enzyme induction by carbamazepine is associated with a small decrease (20%) in milnacipran plasma steady-state concentrations (Puozzo et al, 2002).…”

Selective Serotonin Reuptake Inhibitor Drug Interactions in Patients Receiving Statins

“…33 However, in clinical doses administered to healthy volunteers, 11 days of treatment with fluoxetine elicited no significant inhibition of CYP3A4 activity as studied using erythromycin and alprazolam as substrates. 34 Fluoxetine (20-60 mg/d) did not influence the pharmacokinetics of the CYP3A4 substrate midazolam, either. 35 Sertraline also inhibits CYP3A4 in vitro, 36 but 8 days of treatment of healthy volunteers with clinical doses of sertraline did not significantly alter levels of the CYP3A4 substrates erythromycin and alprazolam.…”

“…35 Sertraline also inhibits CYP3A4 in vitro, 36 but 8 days of treatment of healthy volunteers with clinical doses of sertraline did not significantly alter levels of the CYP3A4 substrates erythromycin and alprazolam. 34 Fluvoxamine inhibited the CYP3A4 substrate tandospirone in an animal model 37 but showed little in vitro effect on this enzyme. 38 Twelve days of treatment with fluvoxamine (200 mg/d) increased the area under the curve of midazolam (a CYP3A4 substrate) by 66%; however, this increase was less than one-tenth of the increase produced by ketoconazole, a strong CYP3A4 inhibitor, and less than one-sixth of the increase produced by nefazodone, another strong inhibitor of this enzyme.…”

“…Unlike the SSRIs, nefazodone is a potent CYP3A4 inhibitor, 34,35 and the combination of nefazodone with simvastatin has been associated with rhabdomyolysis in at least 4 published case reports. [58][59][60][61] A possible interaction between nefazodone and pravastatin has also been reported.…”

Pharmacogenomics of Antidepressants

“…DeVane et al, [94] studied the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4. Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism.…”