Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.
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Li XQ, Andersson TB, Ahlstrom M, Weidolf L
Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.
Drug Metab Dispos. 2004 Aug;32(8):821-7.
- PubMed ID
- 15258107 [ View in PubMed]
- Abstract
The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S-mephenytoin 4'-hydroxylation and R-omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K(i) of 0.4 to 1.5 microM for lansoprazole, 2 to 6 microM for omeprazole, approximately 8 microM for esomeprazole, 14 to 69 microM for pantoprazole, and 17 to 21 microM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP3A4-catalyzed midazolam 1'-hydroxylation (K(i) of 6 and 22 microM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1'-hydroxylation with IC(50) > 200 microM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K(i) values of 6 microM for CYP2C9, 2 to 8 microM for CYP2C19, 12 microM for CYP2D6, and 15 microM for CYP3A4. The inhibitory potency of R-omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S-isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R-enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dexlansoprazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Lansoprazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Lansoprazole Cytochrome P450 2C9 Protein Humans UnknownInhibitorInducerDetails Omeprazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Omeprazole Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Rabeprazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Rabeprazole Cytochrome P450 2C9 Protein Humans UnknownInhibitorDetails Rabeprazole Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Rabeprazole Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareClopidogrelLansoprazole The serum concentration of the active metabolites of Clopidogrel can be reduced when Clopidogrel is used in combination with Lansoprazole resulting in a loss in efficacy. ClopidogrelRabeprazole The serum concentration of the active metabolites of Clopidogrel can be reduced when Clopidogrel is used in combination with Rabeprazole resulting in a loss in efficacy. ClopidogrelDexlansoprazole The serum concentration of the active metabolites of Clopidogrel can be reduced when Clopidogrel is used in combination with Dexlansoprazole resulting in a loss in efficacy. ClopidogrelTegoprazan The serum concentration of the active metabolites of Clopidogrel can be reduced when Clopidogrel is used in combination with Tegoprazan resulting in a loss in efficacy.