Venlafaxine CYP2D6 inhibitors

Administration of the CYP2D6 inhibitor quinidine, 200 mg/day for 2 days, to the extensive metabolizers reduced the oral clearance of venlafaxine to the level seen in poor metabolizers. Quinidine had no effect on venlafaxine clearance in subjects who were poor metabolizers before treatment. The authors suggested that poor metabolizers may be at particular risk of venlafaxine toxicity, as could subjects who take inhibitors of CYP2D6. 

Theoretically the metabolism of venlafaxine may be inhibited by CYP2D6 inhibitors or substrates such as diphenhydramine, melperone, quinidine or thioridazine. CYP3A4 inhibitors such as ketoconazole may also have some effect. An isolated case describes a hypertensive crisis associated with venlafaxine and di-sulfiram. The manufacturers predict that the use of triptans with venlafaxine may have additive effects on serotonin, which could lead to the serotonin syndrome. 

Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

The SNRIs have relatively fewer CYP450 interactions than the SSRIs. Venlafaxine is a substrate but not an inhibitor of CYP2D6 or other isoenzymes, whereas desvenlafaxine is a minor substrate for CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6 and so may elevate TCA and other CYP2D6 substrate levels. Like all serotonergic antidepressants, SNRIs are contraindicated in combination with MAOIs. 

In eight patients with major depressive disorder without psychotic features, who did not respond to serotonin reuptake inhibitors therapy when risperidone was added, all improved within 1 week. Furthermore, risperidone also seemed to have beneficial effects on sleep disturbance and sexual dysfunction (272). In an open study in 30 healthy subjects who took risperidone 1 mg orally before and after venlafaxine dosing to steady state, the oral clearance of risperidone fell by 38% and the volume of distribution by 17%, resulting in a 32% increase in AUC renal clearance of 9-hydroxyrisperidone also fell by 20% (273). The authors concluded that these small effects were consistent with the fact that venlafaxine is unlikely to alter the clearance of risperidone, which is mainly by CYP2D6. 

Women taking tamoxifen should avoid taking drugs (eg, SSRIs) that inhibit CYP2D6. SSRIs such as venlafaxine are preferred treatment of hot flashes because they do not inhibit CYP2D6 paroxetine and fluoxetine should be avoided because they are potent inhibitors of CYP2D6. 

Sertraline, at its usual effective dose of 50 mg/day, has been found to cause less pronounced modifications in plasma concentrations of tricyclic antidepressants (TCAs) as compared with other selective serotonin reuptake inhibitors (SSRIs) (mainly studies with fluoxetine, fluvoxamine, and paroxetine). However, since inhibition of the hepatic enzyme CYP2D6 is dose-dependent, significant increase in plasma concentration of TCAs may occur when higher doses of sertraline are administered. Acute liver damage possibly related to sertraline and venlafaxine ingestion has been reported. 

Although venlafaxine is a weak inhibitor of CYP2D6, variability has been observed in the pharmacokinetic parameters of venlafaxine in patients with hepatic or renal function impairment. As a precaution, elderly patients taking venlafaxine concurrently with a drug that has a narrow therapeutic index and also is metabolized by CYP2D6 should be carefully monitored. Concurrent use of CYP3A4 inhibitors with venlafaxine has been shown to interfere with its metabolism and clearance. Similar to the other antidepressants that block 5-HT reuptake, venlafaxine may interact pharmacodynamically to cause toxic levels of 5-HT to accumulate, leading to the 5-HT syndrome. 

No important interactions normally appear to occur with venlafaxine and ACE inhibitors, beta blockers or diuretics, but an isolated report suggests that propranolol, particularly if it is given with other CYP2D6 substrates, may affect the metabolism of venlafaxine. 

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