Esomeprazole provides more effective acid control than omeprazole, with reduced interpatient variability, thereby offering the potential for improved efficacy in acid-related diseases.

This article reviews the pharmacokinetics of esomeprazole, the (S)-isomer of the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first single isomer PPI developed for the treatment of patients with acid-related diseases. In vitro experiments in human liver microsomes demonstrated that the formation of the hydroxy and 5-O-desmethyl metabolites of esomeprazole is via cytochrome P450 (CYP) 2C19, whereas that of the sulphone metabolite is via CYP3A4. The formation rate of the hydroxy metabolite from esomeprazole is lower than for (R)-omeprazole, but that of the 2 other metabolites is higher, demonstrating stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabo- lites for esomeprazole was one-third of that for (R)-omeprazole, suggesting lower clearance of esomeprazole in vivo. In vivo investigations demonstrated that esomeprazole is chirally stable after administration. Esomeprazole is 97% bound to plasma proteins. In normal (extensive) metabolisers with regard to CYP2C19, esomeprazole is metabolised more slowly than omeprazole, resulting in a higher area under the concentration-time curve (AUC) after administration of the same dose. This is more pronounced after repeated administration rather than after a single dose. In poor metabolisers, the AUC is lower for esomeprazole than for omeprazole, contributing to less overall interindividual variability for esomeprazole than for omeprazole. In general, esomeprazole and omeprazole are subject to the same metabolic transformations. Almost complete recoveries were reported and the ratio between urinary and faecal excretion is about 4:1 for both compounds. The dose-dependent increase in AUC of esomeprazole with repeated administration results from a combination of decreased first-pass elimination and decreased systemic clearance. Patients with gastro-oesophageal reflux disease exhibit a pharmacokinetic pattern similar to that in healthy individuals, whereas elderly individuals exhibited a slightly lower metabolism rate. Patients with a severe deficit in their liver function had a lower rate of metabolism, as would be expected, whereas those with mild to moderate liver disease did not exhibit any alteration in the pharmacokinetics. The pharmacokinetics of esomeprazole in individuals with impaired renal function is unlikely to differ from that in healthy individuals. A slight sex difference in the pharmacokinetics of esomeprazole was demonstrated in that the AUC and peak plasma drug concentration were slightly, but not statistically significantly, higher in females than in males.

The approximately 5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2--neither in PMs nor in EMs.

INTRODUCTIONOmeprazole, the ®rst proton pump (H + , K + -ATPase) inhibitor, has been used for over a decade in the treatment of acid-related diseases. Like subsequent proton pump inhibitors, omeprazole is metabolized primarily by a polymorphically expressed enzyme within cytochrome P450 (CYP), CYP2C19.1 Omeprazole is a racemic composition of its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, which have demonstrated stereoselective metabolisms. 2±4Esomeprazole is metabolized to a lesser degree than R-omeprazole by CYP2C19. Esomeprazole has also been shown to be metabolized at a lower rate, resulting in higher plasma levels, 4 which, because the area under the curve (AUC) directly correlates to the antisecretory effect, 5 promotes more effective acid control. Thus, esomeprazole's inhibitory effect on gastric acid secretion is greater than that of both omeprazole and its R-isomer. We investigated the relations between dose/concentration and response for esomeprazole and omeprazole after single and repeated doses. MATERIALS AND METHODS SubjectsTwelve healthy males, mean age 24 years (range, 20±30 years) and mean weight 75 kg (range, SUMMARY Background: Esomeprazole, the S-isomer of omeprazole, is the ®rst proton pump inhibitor developed as a single isomer for the treatment of acid-related diseases. Aim: To examine the pharmacokinetics and pharmacodynamics of esomeprazole. Methods: In a crossover study, 12 healthy males received 5, 10 or 20 mg of esomeprazole, or 20 mg of omeprazole, once daily over 5 days. The pharmacokinetics and effects on pentagastrin-stimulated peak acid output of esomeprazole and omeprazole were studied on days 1 and 5. Results: The area under the curve (AUC) of both esomeprazole and omeprazole increased from day 1 to

Esomeprazole 40 mg provides greater acid control in more patients and maintains intragastric pH greater than 4 for a longer period than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with symptoms of GERD.