Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4

Xenobiotica. 2012 Jul;42(7):633-40. doi: 10.3109/00498254.2011.653655. Epub 2012 Feb 7.


Inhibitory potential of proton pump inhibitors (PPIs) and famotidine, an H(2) receptor antagonist, on the metabolic activation of clopidogrel was evaluated using recombinant CYP2B6, CYP2C19 and CYP3A4. Formation of the active metabolite from an intermediate metabolite, 2-oxo-clopidogrel, was investigated by liquid chromatography-tandem mass spectrometry and three peaks corresponding to the pharmacologically active metabolite and its stereoisomers were detected. Omeprazole potently inhibited clopidogrel activation by CYP2C19 with an IC(50) of 12.8 μmol/L and more weakly inhibited that by CYP2B6 and CYP3A4. IC(50) of omeprazole for CYP2C19 and CYP3A4 was decreased about two- and three-fold, respectively, by 30-min preincubation with NADPH. Lansoprazole, esomeprazole, pantoprazole, rabeprazole and rabeprazole thioether, a major metabolite, also inhibited metabolic activation by CYP2C19, with an IC(50) of 4.3, 8.9, 48.3, 36.2 and 30.5 μmol/L, respectively. In contrast, famotidine showed no more than 20% inhibition of clopidogrel activation by CYP2B6, CYP2C19 and CYP3A4 at up to 100 μmol/L and had no time-dependent CYP2C19 and CYP3A4 inhibition. These results provide direct evidence that PPIs inhibit clopidogrel metabolic activation and suggest that CYP2C19 inhibition is the main cause of drug-drug interaction between clopidogrel and omeprazole. Famotidine is considered as a safe anti-acid agent for patients taking clopidogrel.

Publication types

  • Comparative Study

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Biotransformation
  • Clopidogrel
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism*
  • Drug Interactions
  • Famotidine / pharmacology*
  • Humans
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism*
  • Proton Pump Inhibitors / pharmacology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology


  • Proton Pump Inhibitors
  • Recombinant Proteins
  • Famotidine
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • Ticlopidine