Abstracts

Rationale: Carbamazepine (CBZ) is an antiepileptic drug prescribed for management of epilepsy, pain and psychiatric disorders. Its metabolism is highly dependent on hepatic enzymes. The formation of the active CBZ-10,11-epoxide (CBZE) mainly by CYP3A4 and its hydrolysis to trans-dihydrodiol is quantitatively the most important metabolic pathway of CBZ. Other two important routes are the formation of 2- and 3-hydroxycarbamazepine by several CYPs (2B6, 3A4, 1A2) and conjugation of CBZ with glucuronic acid. The metabolic profile of CBZ, its narrow therapeutic index and its use in chronic conditions increase the risk of clinically relevant drug-drug interactions (DDIs). This urges the need to better understand and rationalize the potential interactions involving CBZ. Fluoxetine (FLX) is a commonly prescribed antidepressant. In studies with CYP3A in vivo probes like midazolam, triazolam and zolpidem, FLX does not affect CYP3A mediated clearance of probe drugs. However, it has been shown that FLX inhibits the metabolism of CBZ [Clin Pharmacol Ther 1991; 50(1):10-5; Ther Drug Monit 1993; 15(5):405-9]. The present study was designed to rationalize the in vivo DDI between CBZ and FLX and predict DDIs with other psychotropics and CBZ based on in vitro data.Methods: A liquid chromatography-mass spectrometry method was developed to quantify the 2- and 3-hydroxycarbamazepine, trans-dihydrodiol and CBZE from in vitro incubations. The role of individual P450 enzymes in the formation of these metabolites was determined in supersomes and using P450 specific inhibitors in human liver microsomes (HLM). The effect of FLX and other psychotropics on the metabolism of CBZ was tested in HLM and recombinant enzymes. In addition, the Metabolism and Drug Interaction Database was queried to retrieve all reported in vivo studies using CBZ as the object drug and psychotropics as the precipitants.Results: FLX enantiomers did not affect the formation of CBZE (IC₅₀ >400 M) in HLM but both (R)- and (S)-FLX inhibited the production of 3-hydroxycarbamazepine with IC₅₀ values of 28.5 M and 48.2 M, respectively. The literature survey retrieved eight in vivo studies with evident inhibition of CBZ metabolism (i.e., ?20% increase in the area under plasma concentration-time curve or ?20% decrease in clearance), namely, five studies involving antidepressants (FLX, viloxazine, nefazodone), two with antipsychotics (haloperidol, risperidone) and one with a benzodiazepine (clobazam).Conclusions: The in vitro data suggests that the in vivo FLX CBZ interaction results from inhibition of minor CBZ elimination pathways, not CYP3A4 mediated formation of CBZE. FLX likely inhibits the formation of 3-hydroxycarbamazepine by CYP2B6 or by CYP2C19 and CYP2D6 resulting in the in vivo inhibition of CBZ elimination. The literature review emphasizes the lack of clinical data on interactions between CBZ and psychotropics, which are commonly identified as enzyme inhibitors. Conduct of more in vivo DDIs studies that are guided by in vitro evaluation is essential to better determine the clinical significance of DDIs with relevant co-prescriptions.