PII‐50

BACKGROUND/AIMS Domperidone, a peripheral dopamine‐2 receptor antagonist, can exhibit block of cardiac K+ channel and has been associated with drug‐induced long QT syndrome. This drug is also a P‐gp substrate and inhibition of this transporter due to drug‐drug interaction may lead to an increase in intracellular levels of domperidone and an increased risk of drug‐associated toxicity. Our objective was to predict intracardiac concentrations of domperidone under conditions of variable P‐gp activity. METHODS A physiologically based pharmacokinetic (PBPK) model was developed on Matlab® software to predict domperidone disposition in mice. Mainly based on in vitro parameters, this mechanistic model estimates a priori the overall plasma and tissue behaviour under in vivo conditions. Plasma and tissue samples collected at selected time points up to 120 min postdose are obtained after a single i.v injection of 5 mg/kg of H3‐domperidone to male mdr1a/b(‐/‐) and wild type mice. RESULTS PBPK model predictions were in good agreement with experimental results for all tissues and organs considered. Predicted intracardiac domperidone concentrations were higher for mdr1a/b(‐/‐) mice compared to wild type mice suggesting the relevance of the protective function of P‐gp in cardiac tissue. CONCLUSIONS This PBPK model succeeds in the prediction of domperidone disposition in both mice strains. This model can be scaled up to human to predict domperidone distribution behaviour when P‐gp activity is decreased. Clinical Pharmacology & Therapeutics (2005) 79 , P49–P49; doi: 10.1016/j.clpt.2005.12.175