Venlafaxine metabolism

Desvenlafaxine Desmethyi metabolite of venlafaxine, metabolism is by phase II rather than CYP phase I ... 

Rotzinger, S, Bourin, M, Akimoto, Y, Coutts, RT and Baker, GB (1999) Metabolism of some second and fourth generation antidepressants iprindole, viloxazine, buproprion, mianserin, maprotiline, trazodone, nefazodone and venlafaxine. Cell. Molec. Neurobiol. 19 427 42. 

These types of antidepressant were introduced around 10 years after the SSRIs. They include the serotonin noradrenaline reuptake inhibitor venlafaxine and the selective noradrenaline reuptake inhibitor reboxetine. Although there are fewer data about these drugs, clinical experience has shown they are well tolerated and, unlike the SSRIs, they are only weak inhibitors of drug metabolism (Kent, 2000). Depression is a common psychiatric disorder seen in the elderly and often remains untreated or inadequately treated (Forsell and Fastbom, 2000). Venlafaxine was shown to improve the mood in a group of 36 older patients without any effect on cognitive function, an important consideration where there is the possibility of the coexistence of mild or undiagnosed dementia (Tsolaki et al., 2000). 

Pharmacokinetics Venlafaxine is well absorbed (at least 92%) and extensively metabolized in the liver. ODV is the only major active metabolite. Renal elimination of venlafaxine and its metabolites is the primary route of excretion. Venlafaxine ER provides a slower rate of absorption but the same extent of absorption compared with the immediate-release tablet. 

Venlafaxine is metabolized to its active metabolite, ODV, by cytochrome P-450 2D6. Therefore, the potential exists for a drug interaction between venlafaxine and drugs that inhibit this isoenzyme. 

Serotonin re-uptake inhibitors are readily absorbed after oral administration and widely distributed throughout the body. Elimination is mainly by hepatic metabolism. Fluoxetine, sertraline and venlafaxine are demethylated to active metabolites. 

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. 

Venlafaxine is rapidly absorbed following oral administration. Venlafaxine = 5 hours) is metabolized through the CYP450-2D6 and CYP450-3A4 systems to its active metabolite, O-desmethylvenlafaxine = 11 hours), and is excreted through the kidney (Kla-merus et al., 1992). 

Ball, S.E., Ahem, D., Scatina, J., and Kao, J. (1997) Venlafaxine in vitro inhibition of CYP2D6 dependent imipramine and desipra-mine metabolism comparative studies with selected SSRIs, and... 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

The SSRIs, venlafaxine, or nefazodone may be reasonable alternatives to earlier generation antidepressants because of their less problematic side effect profiles (486). The propensity to increase activity, the lack of sedation, gastrointestinal symptoms, and alterations in blood pressure are potential complications, however. Given AIDS-induced altered metabolism, for many of these agents, TDM may be helpful in establishing an effective, nontoxic dose. 

Venlafaxine (Effexor, 11.57) blocks the reuptake of serotonin and norepinephrine from the synaptic junction and acts as an antidepressant (Scheme 11.5). The primary metabolic pathway of venlafaxine is (9-demethylation (11.58), which is mediated by CYP2D6. CYP2D6 has variable activity across different populations. Groups with a more active form of CYP2D6 tend to show more side effects from venlafaxine. 

Venlafaxine + cimetidine —> increased plasma venlafaxine concentration due to impaired metabolism. Increased side effects. 

Cyt 2D6 metabolizes haloperidol, risperidone, thioridazine, sertindole, olanzapine and clozapine common substrates - fluoxetine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, propranolol, metoprolol, timolol, codeine, encainide, flecanide. Common inhibitors - paroxetine, sertraline, fluoxetine. 

Deaths have been described after venlafaxine overdose, but in combination with other agents and alcohol. However, there have been two fatal cases of overdosage in which venlafaxine was the only agent detected postmortem (30). It therefore appears that venlafaxine can occasionally prove fatal in overdosage, probably through cardiac conduction abnormalities and seizures (30,31). It is possible that poor metabolizers may be especially liable to develop toxic effects. 

The effects of venlafaxine on the pharmacokinetics of alprazolam have been investigated in 16 healthy volunteers. Steady-state venlafaxine 75 mg bd did not inhibit CYP3A4 metabolism of a single dose of alprazolam 2 mg (33). 

Venlafaxine is metabolized by CYP2D6. In healthy volunteers the oral clearance of venlafaxine (37.5 mg/ day for 2 days) was fourfold less in poor metabolizers (n = 6) than extensive metabolizers (n = 8) (45). 

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. 

Klockowski PM. Effect of venlafaxine on CYPlA2-depen-dent pharmacokinetics and metabolism of caffeine. J Clin Pharmacol 1999 39(3) 252-9. 

PROPAFENONE I. ANTIARRHYTHMICS - disopyra-mide, procainamide 2. ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS -arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES - terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS - pentamidine isetionate 10. ANTIPSYCHOTICS-atypicals, phenothiazines, pimozide II. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS -parenteral bronchodilators 13. CNS STIMULANTS - atomoxetine Risk of ventricular arrhythmias, particularly torsades de pointes Additive effect these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be t by propafenone. Amitriptyline and clomipramine may t propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other Avoid co-administration... 

BETA-BLOCKERS VENLAFAXINE T plasma concentrations and efficacy of metoprolol, propranolol and timolol Venlafaxine inhibits CYP2D6-mediated metabolism of metoprolol, propanolol and timolol Monitor PR and BP at least weekly watch for metoprolol toxicity (in particular, toss of its cardioselectivity) and propanolol toxicity... 

MAOIs DULOXETINE, VENLAFAXINE Risk of severe hypertensive reactions and of serotonin syndrome > For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome. Duloxetine inhibits the reuptake of both serotonin and norepinephrine. Due to impaired metabolism of these amines, there is an accumulation of serotonin and norepinephrine in the brain and at peripheral sites Do not co-administer duloxetine and venlafaxine prior to 14 days after discontinuing an MAOI, and do not co-administer MAOI for 5 days after discontinuing duloxetine, 1 week after venlafaxine... 

SSRIs METOPROLOL t plasma concentrations of metoprolol SSRIs inhibit metabolism of metoprolol (paroxetine, fluoxetine, sertraline, fluvoxetine, and venlafaxine via CYP2D6 (es)citalopram uncertain at present) Monitor PR and BP closely watch for metoprolol toxicity, in particular loss of its cardioselectivity... 

SNRIs ANTIMALARIALS - ARTEMETHER/ LUMEFANTRINE t artemether/lumefantrine levels with risk of toxicity, including arrhythmias Venlafaxine inhibits CYP3A4, which is partly responsible for the metabolism of artemether Avoid co-administration with venlafaxine and caution with duloxetine... 

VENLAFAXINE HALOPERIDOL t haloperidol levels Inhibited metabolism Avoid co-administration... 

---