Comparative physiologically based pharmacokinetics of hexobarbital, phenobarbital, and thiopental in the rat

Abstract

A physiologically based pharmacokinetic model, which is an extension of the Bischoff-Dedrick multiorgan model, was developed to describe the kinetics of barbiturates (hexobarbital, phenobarbital, and thiopental) in the rat. The model is composed of 11 organ or tissue compartments. The brain compartment was featured as a nonflow-limited organ for some low lipid soluble barbiturates. Michaelis-Menten constants for drug metabolism (K_m, V_max were determined from in vitroexperiments using liver microsomes. Binding of drugs to plasma and tissue proteins was measured in vitrousing an equilibrium dialysis method. Distribution of drugs to red blood cells was measured in vitrowith thiopental exhibiting a concentration dependent distribution. Penetration rates of the barbiturates into the brain were predicted on the basis of their lipid solubilities. A set of mass balance equations included terms for the inflow and outflow of drug carried by the perfusing blood, drug metabolism, protein binding, and penetration rate into the brain as well as blood flow rate and tissue mass. Solution of the system of equations yielded the time courses of drugs in each organ. However, predicted time courses of drugs in plasma and brain were not in good agreement with those observed. Therefore, the tissue to plasma distribution ratios evaluated from in vivoexperiments were substituted for the in vitrovalues, resulting in fairly good agreement between predicted and observed values.