Using human liver microsomes (HLMs) and recombinant CYP450s, we characterized the metabolism of cisapride and documented its inhibitory effect on CYP450s. Two cisapride enantiomers (EI and EII) were separated and fractions collected for study. HPLC chromatograms of HLM incubates of cisapride separated 3 metabolite peaks, M1-M3. The identity of M1 is consistent with norcisapride, while M2 and M3 may represent oxidative hydroxylation of the fluorophenyl ring. The formation rate of M1 and 10μM cisapride in 15 HLMs significantly correlated with the activities of CYP3A, 2C19 and 1A2. Of CYP isoform specific inhibitors tested, ketoconazole potently inhibited the formation of M1, M2 and M3. Of the 10 recombinant CYP450s tested, CYP3A4, 2C8, 2C19, 2C9, 1A2 and 2B6 formed M1. Inhibition by racemic cisapride of CYP2D6 was relatively potent (Ki=14±16μM), of CYP1A2 (Ki=40±12μM) moderate and of CYP3A (Ki=142±27μM) weak. The inhibition by cisapride of CYP2D6 appears to be due to EII as the IC50 (μM) of EII (20±6) was closer to that of racemic cisapride (10±1.8), while that of EI (59±17) was 6-fold higher. In conclusion, cisapride is metabolized by multiple CYP450s in vitro which may make prediction of cisapride drug interaction and cardiac toxicity more difficult than described in the manufacturer's labels. Cisapride appears to inhibit CYP2D6-mediated metabolism in a stereoselective manner.
ASJC Scopus subject areas
- Pharmacology (medical)