Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole

This article reviews the pharmacokinetics of esomeprazole, the (S)-isomer o f the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first sin gle isomer PPI developed for the treatment of patients with acid-related di seases. In vitro experiments in human liver microsomes demonstrated that the format ion of the hydroxy and 5-O-desmethyl metabolites of esomeprazole is via cyt ochrome P450 (CW) 2C19, whereas that of the sulphone metabolite is via CYP3 A4. The formation rate of the hydroxy metabolite from esomeprazole is lower than for (R)-omeprazole, but that of the 2 other metabolites is higher, de monstrating stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabolites for esomeprazole was one-third of that for (R)-omepra zole, suggesting lower clearance of esomeprazole in vivo. In vivo investigations demonstrated that esomeprazole is chirally stable af ter administration. Esomeprazole is 97% bound to plasma proteins. In normal (extensive) metabolisers with regard to CYP2C19, esomeprazole is metabolis ed more slowly than omeprazole, resulting in a higher area under the concen tration-time curve (AUC) after administration of the same dose. This is mor e pronounced after repeated administration rather than after a single dose. In poor metabolisers, the AUC is lower for esomeprazole than for omeprazol e, contributing to less overall interindividual variability for esomeprazol e than for omeprazole. In general, esomeprazole and omeprazole are subject to the same metabolic t ransformations. Almost complete recoveries were reported and the ratio betw een urinary and faecal excretion is about 4 : 1 for both compounds. The dos e-dependent increase in AUC of esomeprazole with repeated administration re sults from a combination of decreased first-pass elimination and decreased systemic clearance. Patients with gasho-oesophageal reflux disease exhibit a pharmacokinetic pattern similar to that in healthy individuals, whereas e lderly 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 pharma cokinetics of esomeprazole in individuals with impaired renal function is u nlikely to differ from that in healthy individuals. A slight sex difference in the pharmacokinetics of esomeprazole was demonstrated in that the AUC a nd peak plasma drug concentration were slightly, but not statistically sign ificantly, higher in females than in males.