Pharmacokinetics and metabolism of omeprazole in animals and man - an overview

Abstract

The pharmacokinetics of omeprazole have been studied to varying extent in the mouse, rat, dog and in man.

The drug is rapidly absorbed in all these species. The systemic availability is relatively high in the dog and in man provided the drug is protected from acidic degradation in the stomach. In man the fraction of the oral dose reaching the systemic circulation was found to increase from an average of 40.3 to 58.2 % when the dose was raised from 10 to 40 mg, suggesting some dose-dependency in this parameter.

The drug distributes rapidly to extra-vascular sites. The volume of distribution, Vβ, in man is comparable to the volume of the extracellular water. The penetration into the red cells is low, the ratio between the concentration in whole blood and in plasma being about 0.6. Omeprazole is bound to about 95% to proteins in human plasma. The binding is lower in the dog and rat (90 and 87%, respectively).

Omeprazole is eliminated almost completely by metabolism and no unchanged drug has been recovered in the urine in the species studied. Two metabolites, characterised as the sulfone and sulfide of omeprazole, have been identified and quantified in human plasma. The mean elimination half-life in man and in the dog is about 1 hour, whereas half-lives in the range of 5 to 15 minutes have been recorded in the mouse. In two studies in man, the mean total body clearance was 880 and 1097 ml × min⁻¹, indicating that omeprazole belongs to the group of high clearance drugs. In the dog, too, the drug appears to be rapidly cleared from the blood, the mean total body clearance being about 10.5 ml × min⁻¹ × kg⁻¹.

In the rat and dog, 20 to 30 % of an i.v. or oral dose of omeprazole is excreted as metabolites in the urine and the remaining fraction is recovered in the faeces within three days after the administration. In man, the excretion of radioactivity via the kidneys is much more efficient and the recoveries in the excreta are approximately the reverse of those in the rat and dog.

In vitro studies with rat liver microsome preparations suggest that omeprazole and cimetidine inhibit cytochrome P-450-mediated metabolic reactions to about the same extent in equimolar concentrations. However, since the molar daily dose of cimetidine will be 25 to 50 times higher than that of omeprazole, the latter might have less influence on the mixed function oxidase system than cimetidine. Results obtained in man with an-tipyrine and aminopyrine support this hypothesis.

Key Words:

• Pharmacokinetics
• disposition
• metabolism
• proteinbinding
• drug interactions
• animals
• man