A PHARMACOKINETIC MODEL DESCRIBING PULSATILE UPTAKE OF ORALLY-ADMINISTERED CARBON-TETRACHLORIDE

Many rodent bioassays have been conducted using oral gavage for delive ry of test chemicals. Highly lipophilic compounds are generally admini stered to rodents dissolved in corn oil, a dosing vehicle shown to inf luence xenobiotic toxicity, carcinogenicity and pharmacokinetics by al tering chemical absorption processes. In this paper, we present a mult i-compartmental description of the gastrointestinal (GI) tract linked to a physiologically based pharmacokinetic (PB-PK) model to describe t he 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 absor ption constant (K-2, 1/h), a bioavailability term (A, unitless), and a compartment emptying time (T, h). The model was parameterized by fitt ing multi-peak blood and exhaled breath chamber concentration-time pro files following oral gavage of CCl4 in corn oil and aqueous vehicles t o male Fischer 344 rats. Successful fitting of experimental data was a ccomplished by varying values of K-a, A, and T until adequate fits wer e obtained. Values of K-a and A required to fit data from aqueous gava ge 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 c onstants and bioavailabilities as well as providing a framework for ge neration of more complete, physiologically-realistic descriptions of o ral absorption. Copyright (C) 1997 Elsevier Science Ireland Ltd.