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 described 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 (Km, Vmax) were determined from in vitro experiments using liver microsomes. Binding of drugs to plasma and tissue proteins was measured in vitro using an equilibrium dialysis method. Distribution of drugs to red blood cells was measured in vitro with 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 course of drugs in plasma and brain were not in good agreement with those observed. Therefore, the tissue to plasma distribution ratios evaluated from in vivo experiments were substituted for the in vitro values, resulting in fairly good agreement between predicted and observed values.

Correction for Nonspecific Binding to Various Components of Ultrafiltration Apparatus and Impact on Estimating In Vivo Rat Clearance for a Congeneric Series of 5-Ethyl, 5-n-Alkyl Barbituric Acids

“…Chiba et al (1990) used the binding of imipramine and desipramine to rat liver microsomes (fu mic ϭ 0.453 and 0.409, respectively) to successfully predict steady-state plasma concentrations. Igari et al (1982) reported similar bindings for hexobarbital and thiopental to microsomes (fu mic ϭ 0.82 and 0.99, respectively) as found currently with similar lipophilic homologs, n-pentyl and n-hexyl barbituric acids (fu mic ϭ 0.95 to 0.73). The effect of physicochemical parameters on microsomal binding from equilibrium dialysis (fu inc ) was demonstrated by Austin et al (2002), resulting in an empirical relationship with LogP/D that predicted the microsomal binding of the barbiturates from this study with fu mic /fu inc ratios between 0.9 and 2.2.…”

Determination and Prediction of Tissue Binding of Prednisolone in the Rabbit

“…Experimental data and simulations have appeared which invalidate these assumptions (32,33). Furthermore, the effective protein fraction was shown to vary with drug concentration in some of the protein media examined (33). In the present study, mingling of data from different species was minimal.…”

“…Particularly strong are arguments against extrapolation of binding data from one species or from one protein concentration to another with the inherent assumptions that binding is independent of these factors. Experimental data and simulations have appeared which invalidate these assumptions (32,33). Furthermore, the effective protein fraction was shown to vary with drug concentration in some of the protein media examined (33).…”

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

“…Table 1, 1, 2, 3, 4,9, 10, 11, 12, 13, 14, 15 summarizes all processes and input parameters relevant for the PBPK models of the six test compounds. A more detailed description of the test compounds and the respective PBPK models can be found in the Supplementary Section SI .…”