The Influence of Multiple-Dose Oxcarbazepine on the Metabolism of Single-Dose Quetiapine. In Vivo Experiment in Rats

Abstract

Objective. Psychiatric and neurologic disorders are susceptible to polypharmacy having a higher risk of developing drug-drug interactions. Quetiapine, a frequently used atypical antipsychotic, is extensively metabolized by cytochrome P450 3A4 isoenzyme, while oxcarbazepine, an antiepileptic drug, analog of carbamazepine, is a mild-to-moderate inducer of the same isoenzyme. This study aimed to assess the presence of a pharmacokinetic interaction between quetiapine single-dose and oxcarbazepine multiple-dose, as pretreatment, compared to quetiapine single-dose alone in rats. Methods. The in vivo experiment was carried out on two groups consisting of 12 Wistar albino rats each. The control group was given a single oral dose of quetiapine 85 mg/kg. The test group received oxcarbazepine 80 mg/kg/day, orally, for 5 days followed by a single dose of quetiapine 85 mg/kg. A validated LC-MS/MS method was developed to determine the plasma concentration of quetiapine and its active metabolite, norquetiapine, concomitantly. Non-compartmental analysis was employed to determine the pharmacokinetic parameters of quetiapine and norquetiapine. Results. Short-term administration of oxcarbazepine determined a significant increase in the systemic exposure of norquetiapine by increasing its peak plasma concentration and the total area under the concentration-time curve by 88.85% and 5.29-fold. The expected enzyme-inducing properties of oxcarbazepine were not visible on the quetiapine’s pharmacokinetic profile, producing, although statistically insignificant, an increase in its exposure. Conclusions. The present experiment showed that the administration of oxcarbazepine can determine some changes in the pharmacokinetics of quetiapine and norquetiapine in vivo.