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 Ki of 0.4 to 1.5 μM for lansoprazole, 2 to 6 μM for omeprazole, ∼8 μM for esomeprazole, 14 to 69 μM for pantoprazole, and 17 to 21 μM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4′-hydroxylation and CYP3A4-catalyzed midazolam 1′-hydroxylation (Ki of 6 and 22 μM, 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 IC50 > 200 μM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with Ki values of 6 μM for CYP2C9, 2 to 8 μM for CYP2C19, 12 μM for CYP2D6, and 15 μM 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.
Footnotes
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ABBREVIATIONS: DDI, drug-drug interaction; P450, cytochrome P450; PPI, proton pump inhibitor; AUC, area under the plasma concentration-time curve; PM, poor metabolizer; HLM, human liver microsomes; EM, extensive metabolizer; FWHM, full-width half maximum.
- Received November 10, 2003.
- Accepted March 23, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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