Titre du document / Document title

Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities

Auteur(s) / Author(s)

LI Xue-Qing ⁽¹⁾ ; ANDERSSON Tommy B. ⁽¹⁾ ; AHLSTRÖM Marie ⁽¹⁾ ; WEIDOLF Lars ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ DMPK and Bioanalytical Chemistry, AstraZeneca R&D, Mölndal, SUEDE

Résumé / Abstract

The human clearance of proton pump inhibitors (PPls) 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 PPls (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 PPls showed competitive inhibition of CYP2C19 activity with K₁ 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 (K_l of 6 and 22 μM, respectively), which were at least 2 times more potent than the other PPIs. All PPls 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 K_i 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 PPls, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.

Revue / Journal Title

Drug metabolism and disposition   ISSN 0090-9556   CODEN DMDSAI 

Source / Source

2004, vol. 32, n^o8, pp. 821-827 [7 page(s) (article)] (40 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, ETATS-UNIS  (1973) (Revue)

Mots-clés anglais / English Keywords

Proton pump inhibitor ; Enzyme inhibitor ; Enzyme ; Hydrolases ; H⁺/K⁺-exchanging ATPase ; Benzimidazole derivatives ; In vitro ; Liver ; Antiulcer agent ; Antisecretory agent ; Cytochrome P450 ; Human ; Pantoprazole ; Lansoprazole ; Esomeprazole ; Omeprazole ; Enzymatic activity ; Comparative study ; Rabeprazole ;

Mots-clés français / French Keywords

Inhibiteur pompe proton ; Inhibiteur enzyme ; Enzyme ; Hydrolases ; H⁺/K⁺-exchanging ATPase ; Benzimidazole dérivé ; In vitro ; Foie ; Antiulcéreux ; Antisécrétoire ; Cytochrome P450 ; Homme ; Pantoprazole ; Lansoprazole ; Esoméprazole ; Oméprazole ; Activité enzymatique ; Etude comparative ; Rabéprazole ;

Mots-clés espagnols / Spanish Keywords

Inhibidor bomba protón ; Inhibidor enzima ; Enzima ; Hydrolases ; H⁺/K⁺-exchanging ATPase ; Benzimidazol derivado ; In vitro ; Hígado ; Antiulceroso ; Antisecretorio ; Citocromo P450 ; Hombre ; Pantoprazol ; Lansoprazol ; Esomeprazol ; Omeprazol ; Actividad enzimática ; Estudio comparativo ; Rabeprazol ;

Localisation / Location

INIST-CNRS, Cote INIST : 16545, 35400011386340.0090