In‐vitro characterization of the metabolism of prochlorperazine

Background Prochlorperazine (PCZ) is an antiemetic widely used in the management of nausea and vomiting. PCZ is reported to be extensively metabolized via the CYP450 system. However, the specific CYP450 isoforms responsible have not been identified and only two metabolites have been characterized (sulphoxide n‐oxide, N‐desmethyl). Purpose To identify the metabolites of PCZ and quantify the relative contribution of the CYP450 enzymes involved in their metabolism. Methods 100 μM PCZ was incubated in cDNA (control, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, 2E1) with NADPH, at 37°C for 60 minutes. The reaction was halted with 100 μL of ice cold ACN. The samples were centrifuged at 2000g for 5 minutes and then the supernatant was analyzed by mass spectrometry. PCZ standard curve ranged from 6.25–100 μM. The detection of metabolites by LCMS was aided by the presence of a chlorine isotopic pattern (1:0.33). LC/MS/MS was used to postulate the identities of the metabolites formed by the CYP isoforms. Results The percent loss of PCZ compared to control for each of the CYP450 isoforms is illustrated below. The seven PCZ metabolites identified are: sulphoxide n‐oxide, hydroxy‐nor, desulfonated, hydroxide isomers (2), N‐desmethyl, and sulphoxide. The latter three metabolites appear to be the most prevalent. Conclusions Of the various CYP450s that contribute to PCZ metabolism, CYP2D6 and CYP2C19 are the most efficient. N‐desmethyl PCZ was the major metabolite formed by CYP2D6 and CYP2C19. Clinical Pharmacology & Therapeutics (2004) 75 , P85–P85; doi: 10.1016/j.clpt.2003.11.324 Contribution of CYP450 Isoforms to the Metabbolism of Prochlorperazine