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 tissues in the rat. The compartments included in the model were brain, heart, gut, liver, muscle, fat, venous blood, arterial blood, and a mass-balance compartment. Drug delivery to the tissues was assumed to be flow limited. The model incorporated a nonsaturable binding site for cocaine in the liver. Elimination occurred via both blood and hepatic elimination. 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 fit was observed following intravenous administration. Future models incorporating non-constant blood flow and pharmacodynamics need to be developed.
Bonate
P L
PL
Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston 77030, USA.
Swann
A
A
Silverman
P B
PB
D000818:Animals; D003042:Cocaine / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014018:Tissue Distribution
D003042:Cocaine