Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin

Clin Pharmacol Ther. 1997 Oct;62(4):384-91. doi: 10.1016/S0009-9236(97)90116-8.


Background: The metabolism of omeprazole includes hydroxylation catalyzed by CYP2C19 and, to a minor extent, sulfoxidation, presumably by CYP3A4. Sulfoxidation may be the predominant pathway in individuals devoid of the genetically determined CYP2C19 activity. Ketoconazole is a known CYP3A4 inhibitor in daily doses from 200 to 400 mg. In this study ketoconazole was used as a probe to investigate the extent to which CYP3A4 is involved in omeprazole metabolism in vivo.

Methods: A single oral 20 mg dose of omeprazole before and after four daily doses of 200, 100, or 50 mg ketoconazole was given to 10 healthy subjects, previously phenotyped as poor or extensive metabolizers of S-mephenytoin. Concentrations of omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, and ketoconazole were analyzed with reversed-phase HPLC methods in plasma samples collected repeatedly for 12 hours after dosing.

Results: After intake of 20 mg omeprazole with 0, 50, 100, and 200 mg ketoconazole, mean values for omeprazole sulfone area under the plasma concentration versus time curve from 0 to 6 hours [AUC(0-6)] were 482, 206, 167, and < 100 nmol/ in extensive metabolizers and 3160, 2430, 937, and 534 nmol/ in poor metabolizers, respectively. Mean omeprazole AUC(0-6) increased from 1660 to 2265 nmol/ in extensive metabolizers and from 7715 to 15319 nmol/ in poor metabolizers after intake of 200 mg ketoconazole.

Conclusions: An oral daily dose of 100 to 200 mg ketoconazole is sufficient to provide a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers and leads to a doubling of omeprazole levels in poor metabolizers, whereas 50 mg ketoconazole provides only partial inhibition. We concluded that CYP3A4 catalyzes the sulfoxidation of omeprazole and that this is the predominant metabolic pathway of omeprazole in poor metabolizers of S-mephenytoin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Ulcer Agents / administration & dosage
  • Anti-Ulcer Agents / pharmacokinetics*
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / pharmacokinetics*
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacology*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Female
  • Humans
  • Ketoconazole / administration & dosage
  • Ketoconazole / pharmacology*
  • Male
  • Mephenytoin / administration & dosage
  • Mephenytoin / pharmacokinetics*
  • Middle Aged
  • Mixed Function Oxygenases / metabolism*
  • Omeprazole / administration & dosage
  • Omeprazole / pharmacokinetics*
  • Oxidation-Reduction / drug effects
  • Time Factors


  • Anti-Ulcer Agents
  • Anticonvulsants
  • Antifungal Agents
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Omeprazole
  • Mephenytoin
  • Ketoconazole