Pharmacokinetics of Omeprazole and Metabolites Following Single Intravenous and Oral Doses of 40 and 80mg

Summary

This study was performed to investigate the influence of dose on the kinetics of omeprazole and 2 main primary metabolites in plasma. 10 healthy subjects were given solutions of 40 and 80mg omeprazole, orally and intravenously on 4 different occasions, and plasma concentrations were followed for 8 hours. The 4 experiments were performed in random order.

The kinetics following intravenous administration were nonlinear in the dose range 40 to 80mg, resulting in a 19% lower clearance and a 16% longer elimination half-life (0.81 versus 0.70 hours) for the 80mg dose compared to the 40mg dose. Following oral administration of a solution of omeprazole the AUC increased disproportionally when increasing the dose from 40 to 80mg. The nonlinear kinetics at higher dose levels of omeprazole appear mainly to be a result of partial saturation of the transformation of omeprazole into hydroxyomeprazole. The further metabolism of this metabolite exhibited linear kinetics. On the other hand, the formation of omeprazole-sulphone did not appear to be saturable in the dose range studied while its further metabolism seemed to be. The slight dose-dependency in clearance has no clinical relevance for the parenteral use of omeprazole — a drug with a wide therapeutic range. Furthermore, since omeprazole is given orally as slowly absorbed enteric-coated granules in lower doses the potential for dose-dependent kinetics would be much less in the clinical situation than in the present investigation.