A detailed model describing the absorption and pharmacokinetics of omeprazole and its main metabolites, hydroxyomeprazole and omeprazole sulphone, was built using GastroPlus™ (Simulations Plus, Inc.). The program’s Advanced Compartmental and Transit (ACAT) model described the absorption; the pharmacokinetics of all compounds was simulated with a physiologically-based pharmacokinetics (PBPK) model. The metabolic clearance of omeprazole and its metabolites in gut and liver was estimated from in vitro enzyme kinetic constants for CYP3A4, 2C9 and 2C19 combined with built-in in vitro values for the distribution of 3A4 in gut and the average expressions of all three enzymes in liver or fitted to observed in vivo plasma concentration-time (Cp-time) profiles. The model accurately described pharmacokinetics of each compound after different intravenous (IV) and oral (PO) doses of omeprazole in different populations of subjects. The model was then used to predict the effect of fluvoxamine on the pharmacokinetics of omeprazole in extensive and poor metabolizers, accounting for varying contributions of the fluvoxamine-omeprazole and omeprazole-metabolite drug-drug interactions in each group of subjects.
ADMET Europe 2010 Conference, April 8-9, 2010, Munich, Germany
By Viera Lukacova, Neil Parrot, Martin Howard, Walter Woltosz , Michael Bolger