Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities

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.

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

“…Keywords CYP2C19, omeprazole, gender, Korean, Swedes [2] , proguanil [3] and proton pump inhibitors (PPIs) [4]. The major metabolites of omeprazole detected in vivo in human plasma are 5-hydroxyomeprazole formed by CYP2C19 and omeprazole sulphone formed by CYP3A4 [5,6].…”

Steroid Psychosis: A Case Series of Three Patients

“…2,5 In the first two cases use of cytochrome P450 enzyme inhibitors like doxycycline, hydroxychloroquine, pantoprazole and esomeprazole could have also contributed to the development of psychosis. 8,9,10,11 Various treatment approaches are available for steroid induced psychosis. The most widely used and effective treatment strategy is to taper and discontinue steroids where possible.…”

Actual Aspects of Anti-Secretor Therapy of Gastroesophageal Reflux Disease

“…Сульфенамид с помощью дисульфидных свя-зей ковалентно связывается с цистеиновыми группами протонной помпы, что приводит к ингибированию H+/ K+-АТФазы и угнетению секреции HCl. Ключевую роль в метаболизме ИПП играет изоформа CYP 2C19 цитохрома P450, ее роль сводится к биотрансформации ИПП в неак-тивные метаболиты -инактивации [18,19].…”