We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers. Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng.ml-1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability. Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment. The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.

Conventional antidepressant treatment fails for up to 30% of patients with major depression. When there are concomitant psychotic symptoms, response rates are even worse. Thus, subsequent treatment often includes combinations of antidepressants or augmentation with antipsychotic agents. Atypical antipsychotic agents such as olanzapine cause fewer extrapyramidal adverse effects than conventional antipsychotics; for that reason, they are an advantageous augmentation strategy for treatment-resistant and psychotic depression. The purpose of this study was to assess the potential for pharmacokinetic interaction between olanzapine and fluoxetine, a popular antidepressant that is a selective serotonin reuptake inhibitor. The pharmacokinetics of 3 identical single therapeutic doses of olanzapine (5 mg) were determined in 15 healthy nonsmoking volunteers. The first dose of olanzapine was taken alone, the second given after a single oral dose of fluoxetine (60 mg), and the third given after 8 days of treatment with fluoxetine 60 mg, qd. Olanzapine mean C max was slightly higher (by about 18%) and mean CL/F was slightly lower (by about 15%) when olanzapine was coadministered with fluoxetine in single or multiple doses. Olanzapine mean t ½ and median t max did not change. Although the pharmacokinetic effects of fluoxetine on olanzapine were statistically significant, the effects were small and are unlikely to modify olanzapine's safety profile. The mechanism of influence is consistent with an inhibition of CYP2D6, which is known to control a minor pathway of olanzapine metabolism.Olanzapine (molecular weight: 312.43) is a potent dopamine and serotonin antagonist with anticholinergic and antihistaminic activity. It is marketed under the trade name Zyprexa and is classified as an atypical antipsychotic agent.3 The major metabolite of olanzapine in the urine and plasma has been identified as the 10-Nglucuronide of olanzapine. Other metabolic pathways involve flavin-containing monooxygenases and at least 2 specific cytochrome P450 isoenzymes: CYP1A2 and CYP2D6. 4 Fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI), is extensively metabolized in the liver to form norfluoxetine, an active metabolite, and other metabolites. It has been shown that fluoxetine and norfluoxetine inhibit CYP2D6 in liver tissue preparations. 5,6Because CYP2D6 is one of the pathways of olanzapine metabolism, and various metabolic pathways for fluoxetine may compete with those for olanzapine, fluoxetine might influence the pharmacokinetic profile of olanzapine. Because atypical antipsychotic and SSRI antidepressant drugs may be prescribed together, this study was conducted to evaluate the influence of fluoxetine, after single and repeated administration, on the pharmacokinetic characteristics of olanzapine after a single dose in healthy volunteers. MATERIALS AND METHODS

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