Olanzapine metabolism

In 11 healthy volunteers carbamazepine (400 mg/day for 2 weeks) reduces by about 30% the AUC of olanzapine, presumably by induction of olanzapine metabolism (104). Although the interaction was considered of little relevance, it cannot be excluded that some patients on carbamazepine may require higher olanzapine dosages than usual. 

Fluvoxamine inhibits the cytochrome P450 isoenzyme CYP1A2, which is the major isoenzyme involved in the metabolism of olanzapine, resulting in increased olanzapine levels and adverse effects. All SSRIs affect CYP2D6 (to differing extents). This isoenzyme has a minor role in olanzapine metabolism, and therefore SSRIs other than fluvoxamine have only a small effect on olanzapine levels. 

A polymorphism in P450 3A43 has been used to explain a racial difference in olanzapine clearance [1534], The conclusion is surprising in that another study reported that P450s 1A2 and 2D6 (and FMO) are more involved in olanzapine metabolism [1535]. 

Olanzapine Valproate induces olanzapine metabolism slightly, but in extreme situations (high valproate concentrations and/ or low olanzapine doses) the effect could be clinically important [350 j. 

Oral The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (eg, nonsmoking women 65 years of age and older), or who may be more pharmacodynamically sensitive to olanzapine. 

Special populations Use a starting dose of 6 mg/25 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine/fluoxetine (eg, female gender, elderly, nonsmoking status). When indicated, perform dose escalation with caution in these patients. Olanzapine/fluoxetine has not been systemically studied in patients older than 65 years of age or in patients younger than 18 years of age. 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

This group includes risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole. But all these agents cause dose-related EPS and appear in general more likely to cause diabetes and other metabolic problems than some of the older drugs (see Duggan et ah, 2005). 

Olanzapine is metabolized by several pathways and is therefore unlikely to be affected by concurrent administration of other medications. Because olanzapine does not appear to inhibit any cytochrome P450 enzymes, it should not increase the availability of other medications through inhibition of such enzymes. Additive pharmacodynamic effects are expected if olanzapine is combined with medications that also have anticholinergic, antihistaminic, or aj-adrenergic side effects. 

The receptor properties of quetiapine are similar to those for olanzapine and risperidone. This medication is rapidly absorbed, reaching peak plasma concentrations in 1.5 hours. It is metabolized by the liver. 

Recall that one of the key drug-metabolizing enzymes is the cytochrome P450 (CYP450) enzyme called 1A2. Two atypical antipsychotic drugs are substrates of 1A2, namely olanzapine and clozapine. That means that when they are given con-... 

Insulin resistance is a major but not necessary risk factor for type 2 diabetes. Glucose metabolism in 36 out-patients with schizophrenia aged 18-65 years taking clozapine (n — 12), olanzapine (n — 12), or risperidone (n = 12) has been examined in a cross-sectional study... 

Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients metabolic outcomes after 1 year. J Clin Psychiatry 2002 63(5) 425-33. 

Lasser RA, Mao L, Gharabawi G. Smokers and nonsmokers equally affected by olanzapine-induced weight gain metabolic implications. Schizophr Res 2004 66 163-7. 

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. 

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