Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro

Bryan A. Ward, Alan Morocho, Abdullah Kandil, Raymond E. Galinsky, David A. Flockhart, Zeruesenay Desta

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Aims: To confirm the identity of the major metabolites of domperidone and to characterize the cytochrome P450s (CYPs) involved in their formation. Methods: Human liver microsomes (HLMs) were used to characterize the kinetics of domperidone metabolism and liquid chromatography-mass spectrometry to identify the products. Isoform-specific chemical inhibitors, correlation analysis and expressed human CYP genes were used to identify the CYPs involved in domperidone oxidation. Results: In HLMs, domperidone underwent hydroxylation to form 5-hydroxydomperidone (MIII) and N-dealkylation to form 2,3-dihydro-2-oxo-1H- benzimidazole-1-propionic acid (MI) and 5-chloro-4-piperidinyl-1,3-dihydro- benzimidazol-2-one (MII). The formation of all three metabolites (n = 4 HLMs) followed apparent Michaelis-Menten kinetics. The mean Km values for MI, MII and MIII formation were 12.4, 11.9, and 12.6 μm, respectively. In a panel of HLMs (n = 10), the rate of domperidone (5 μm and 50 μm) metabolism correlated with the activity of CYP3A (r > 0.94; P < 0.0001). Only ketoconazole (1 μm) (by 87%) and troleandomycin (50 μm) (by 64%) inhibited domperidone (5 μm) metabolism in HLMs. Domperidone (5 and 50 μm) hydroxylation and N-dealkylation was catalyzed by expressed CYP3A4 at a higher rate than the other CYPs. CYP1A2, 2B6, 2C8 and 2D6 also hydroxylated domperidone Conclusions: CYP3A-catalyzed N-dealkylation and aromatic hydroxylation are the major routes for domperidone metabolism. The drug would be expected to demonstrate highly variable bioavailability due to hepatic, and possibly intestinal first-pass metabolism after oral administration. Increased risk of adverse effects might be anticipated during concomitant administration with CYP3A inhibitors, as well as decreased efficacy with inducers of this enzyme.

Original languageEnglish (US)
Pages (from-to)277-287
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume58
Issue number3
DOIs
StatePublished - Sep 1 2004

Keywords

  • Cytochrome P450
  • Domperidone
  • Hydroxylation
  • Metabolites
  • Prokinetic

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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