A pharmacokinetic model describing pulsatile uptake of orally-administered carbon tetrachloride

Many rodent bioassays have been conducted using oral gavage for delivery of test chemicals. Highly lipophilic compounds are generally administered to rodents dissolved in corn oil, a dosing vehicle shown to influence xenobiotic toxicity, carcinogenicity and pharmacokinetics by altering chemical absorption processes. In this paper, we present a multi-compartmental description of the gastrointestinal (GI) tract linked to a physiologically based pharmacokinetic (PB-PK) model to describe the complex oral uptake of carbon tetrachloride (CCl4) administered in corn oil and 0.25% Emulphor(R). The GI submodel was described using a series of subcompartments, each subcompartment described with an absorption constant (K-2, 1/h), a bioavailability term (A, unitless), and a compartment emptying time (T, h). The model was parameterized by fitting multi-peak blood and exhaled breath chamber concentration-time profiles following oral gavage of CCl4 in corn oil and aqueous vehicles to male Fischer 344 rats. Successful fitting of experimental data was accomplished by varying values of K-a, A, and T until adequate fits were obtained. Values of K-a and A required to fit data from aqueous gavage were greater than corn oil. Utilization of the multi-compartmental GI tract submodel provided increased precision in fitting complex oral uptake profiles compared to previously used one- and two-compartment oral uptake models. This model provides estimates of absorption rate constants and bioavailabilities as well as providing a framework for generation of more complete, physiologically-realistic descriptions of oral absorption. Copyright (C) 1997 Elsevier Science Ireland Ltd.