PRELIMINARY PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR COCAINE IN THE RAT - MODEL DEVELOPMENT AND SCALE-UP TO HUMANS

A physiologically based multicompartmental model has been developed to describe the concentration-time course of cocaine in plasma and tissu es in the rat. The compartments included in the model were brain, hear t, gut liver, muscle, fat, venous blood, arterial blood, and a mass-ba lance compartment. Drug delivery to the tissues was assumed to be flow limited. The model incorporated a nonsaturable binding site for cocai ne in the liver. Elimination occurred via both blood and hepatic elimi nation. The model was validated using independently derived data. The model was scaled to humans and accurately predicted the cocaine levels following intranasal and inhalation administration. However, a poor f it was observed following intravenous administration. Future models in corporating non-constant blood flow and pharmacodynamics need to be de veloped.