Effect of High‐Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long‐lasting Inhibition of CYP2C19

Abstract

In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.5 mg midazolam, and 50 mg caffeine as respective index substrates for CYP2C19, 3A4, and 1A2 before and 1, 25, 49 (pantoprazole only), and 73 hours after an 8-day pretreatment with 80 mg esomeprazole twice daily. The area under the plasma concentration-time curve (AUC) of R-pantoprazole increased 4.92-fold (90% confidence interval (CI) 3.55-6.82), 2.31-fold (90% CI 1.85-2.88), and 1.33-fold (90% CI 1.06-1.68) at the 1-hour, 25-hour, and 73-hour phases, respectively, consistent with a substantial and persistent inhibition of CYP2C19. The AUC of midazolam increased up to 1.44-fold (90% CI 1.22-1.72) and the paraxanthine/caffeine metabolic ratio up to 1.19-fold (90% CI 1.04-1.36), when the index substrates were taken 1 hour after esomeprazole. Based on the recovery of R-pantoprazole oral clearance, the turnover half-life of CYP2C19 was estimated to average 53 hours. Pharmacokinetic simulation based on the observed concentrations of esomeprazole and its metabolites as well as their published CYP2C19 inhibitory constants was well in line with the observed changes in R-pantoprazole pharmacokinetics during the course of the study. Extrapolations assuming linear pharmacokinetics of esomeprazole suggested weak to moderate inhibition at 20 and 40 mg twice daily dosing. In conclusion, high-dose esomeprazole can cause strong inhibition of CYP2C19, but only weakly inhibits CYP3A4 and leads to minor induction of CYP1A2. The enzymatic activity of CYP2C19 recovers gradually in ~ 3-4 days after discontinuation of esomeprazole treatment.

Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

“…25 We removed the mechanism-based inhibition of CYP3A by esomeprazole, leaving only reversible inhibition as the literature does not report irreversible inhibition of CYP3A by esomeprazole. 28,29 Based on the validation results, our esomeprazole model was consistent with the data observed in the literature.…”

“…However, both inhibitions of CYP2C19 were kept in the model because it is accepted in the literature that esomeprazole is a CYP2C19 reversible and irreversible inhibitor. 28,29 Moreover, the Cl R was changed from 0.037 to 0 L/h, as well as for 5-OH-omeprazole, to be consistent with Simcyp TM built-in library model of omeprazole (Table 2). Indeed, the published PBPK model of esomeprazole considered that Cl R was similar for both enantiomers and omeprazole is a racemic mixture.…”

“…8,26,27 Published data indeed suggest a short-term effect of esomeprazole on midazolam concentration but no irreversible CYP3A inhibition, even with twice the dose used for the current simulation. 28,29 The irreversible inhibition of CYP3A4 by esomeprazole (mechanismbased inhibition) was thus removed from the simulation. However, both inhibitions of CYP2C19 were kept in the model because it is accepted in the literature that esomeprazole is a CYP2C19 reversible and irreversible inhibitor.…”

Drug metabolism in severe chronic obstructive pulmonary disease: A phenotyping cocktail study

“…Omeprazole inhibits CYP2C19 at high concentrations and may exaggerate the apparent effect of disease on CYP2C19. 36 This study was not powered to compare differences in clearance between probe drugs; therefore, it remains unclear whether COPD selectively modulates drug metabolising enzymes or this is an artefact of different probe drugs.…”

“…It is therefore surprising that caffeine was so markedly affected by COPD in this study as drugs with minimal first‐pass metabolism are typically less sensitive to changes in hepatic clearance. Omeprazole inhibits CYP2C19 at high concentrations and may exaggerate the apparent effect of disease on CYP2C19 36 …”