Pipamperone metabolism by various recombinant cytochrome preparations

INTRODUCTION : The evaluation of pharmacokinetic interactions is based on the knowledge of enzymatic metabolization by cytochrome 450 enzymes or cellular transport processes. Research on the metabolism of pipamperone, an antipsychotic of the butyrophenone family, has not yet yielded conclusive results. In the present in vitro study, human cytochrome enzymes were investigated for their possible involvement in the metabolism of pipamperone.

METHODS: The recombinant human cytochrome enzymes tested, i.e. CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, were commercially available. The U.S. Food and Drug Administration-recommended clinical index substrates were used to establish appropriate incubation conditions for each enzyme. All substrates and their metabolites were analyzed by gas chromatography-mass spectrometry. After incubation, the amount of metabolites formed and the concentration of remaining pipamperone were measured. In addition, the metabolites from these in vitro experiments were compared with the metabolites found in the urine of pipamperone-treated patients and with those produced in a cell culture experiment.

RESULTS: Overall, various cytochrome enzymes showed a low turnover of pipamperone. Only CYP2D6 and CYP3A4 caused statistically significant changes in both a decrease in pipamperone concentrations and an increase in metabolites. CYP3A4 proved to be the isoform that metabolized pipamperone most strongly, producing the same metabolite as all other CYP isoenzymes. It is noteworthy that this and other metabolites were also detected in the patients' urine samples.

CONCLUSIONS: Our results suggest that, alongside the tested cytochrome enzymes, other phase I metabolizing systems likely play a role in pipamperone metabolism.