Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4′-hydroxylation*

Abstract

The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole.

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

“…For omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole, plasma f u was 0.05, 0.03, 0.03, 0.02, 0.02, and 0.04, respectively. Unless otherwise indicated, plasma C max (C max,u ) values for each PPI were based on those reported for a specific diazepam drug interaction; 0.3 (0.02) M after 20 mg of oral omeprazole, 5.2 (0.16) M after 30 mg of oral esomeprazole, 3.4 (0.11) M after 60 mg of oral lansoprazole, 4.0 (0.08) M after 90 mg of oral dexlansoprazole, 57 (1.1) M after 240 mg of IV pantoprazole, and 0.45 (0.02) M after 20 mg of oral rabeprazole (see Supplemental Table S2) (Andersson et al, 1990(Andersson et al, , 2001Lefebvre et al, 1992;Ishizaki et al, 1995;Gugler et al, 1996;Vakily et al, 2009). Equation 6 yielded the following estimates for C max,portal : 1.7 M (omeprazole), 15.5 M (esomeprazole), 4.8 M (lansoprazole), 57 M (pantoprazole), and 0.8 M (rabeprazole).…”

“…Furthermore, correction for plasma f u , consideration of portal concentration, use of HLM versus rCYP2C19, and substrate type did not improve the prediction. It should be noted that the rate constant for Ishizaki et al (1995). e Percentage of inhibition in vivo was calculated based on the AUC i /AUC c ratio reported by Andersson et al (1990).…”

“…The AUC of diazepam is increased 1.8-to 2.3-fold in CYP2C19 PM versus extensive metabolizer (EM) subjects, so the drug can serve as a CYP2C19 probe (Andersson et al, 1990;Ishizaki et al, 1995). Moreover, diazepam is a low clearance compound (0.29 -0.46 ml/min per kg), with good oral bioavailability, and undergoes extensive metabolism (Ͼ99% of the dose) (Klotz et al, 1975).…”

“…The diazepam AUC i /AUC c ratio (observed) with each PPI (AUC in the presence of PPI versus placebo) has been reported [90% confidence interval (CI)]; 1.28 (1.19, 1.39; Ishizaki et al, 1995) and 1.36 (1.19, 1.53; Andersson et al, 1990) for omeprazole; 1.12 (0.99, 1.23) for lansoprazole (Lefebvre et al, 1992); 1.81 (1.42, 2.31) for esomeprazole (Andersson et al, 2001) (Gugler et al, 1996); and 0.91 (0.81, 1.02) for rabeprazole (Ishizaki et al, 1995). The CI (90%) was reported or estimated from the mean Ϯ S.D.…”

Interaction between clopidogrel and proton pump inhibitors

“…8 In contrast with omeprazole, rabeprazole showed no inhibition in the metabolism of diazepam, a substrate for cytochrome P450 2C19. 9 Although the metabolite rabeprazole thioether is a potent in vitro inhibitor of cytochrome P450 2C19, its concentration in vivo is about 30% of that of its parent compound. 8,10 Given these differences, it is far from clear that rabeprazole would exhibit an interaction potential with clopidogrel comparable to that of omeprazole and lansoprazole.…”