Effect of dosing vehicles on the pharmacokinetics of orally administered carbon tetrachloride in rats

Abstract

The primary objectives of this investigation were to determine whether oil and aqueous dosage vehicles alter the pharmacokinetics of orally administered carbon tetrachloride (CCl4) in rats, and to relate vehicle effects on CCl4 absorption and bioavailability to alterations of the acute hepatotoxicity of CCl4 seen in a companion study (H.J. Kim, S. Odend'hal, and J. V. Bruckner, 1990, Toxicol. Appl. Pharmacol. 102, 34-49). Fasted 200- to 230-g male Sprague-Dawley rats with indwelling arterial cannulas received 25 mg CCl4/kg body wt by gavage: in corn oil; as an Emulphor aqueous emulsion; in water; and as pure undiluted chemical. The 25 mg/kg dose was also given iv in PEG 400 through an indwelling jugular cannula. Serial blood samples were taken from the iv and gavage animals and analyzed for CCl4 content to obtain blood concentration-versus-time profiles. CCl4 was absorbed very rapidly from the GI tract, as peak concentrations of CCl4 in the blood were reached within 3-6 min of dosing in the aqueous emulsion and water groups. These peak levels were higher than those in the undiluted CCl4 group and substantially higher than those in the corn oil group. Corn oil markedly delayed the absorption of CCl4 from the GI tract and produced secondary peaks in the blood concentration-versus-time profiles. Elimination of CCl4 from the bloodstream of the iv group followed a triexponential pattern. CCl4 was eliminated from the blood at approximately the same rate in the iv and po groups, as reflected by similar elimination rate constant and half-life values. There was a high degree of correlation of both Cmax and AUC0(120) with hepatotoxicity. CCl4 was apparently less acutely hepatotoxic in corn oil due to delay and prolongation of CCl4 absorption, resulting in a marked decrease in the concentration of the chemical in the arterial blood. These findings suggest that corn oil has sufficient effect on the pharmacokinetics of orally administered CCl4 to require an appraisal of its use in studies of the acute oral toxicity of CCl4 and other volatile organic chemicals (VOCs). The use of aqueous Emulphor emulsions appears appropriate in studies of VOC contaminants of drinking water, in that the emulsion did not substantially alter the pharmacokinetics or hepatotoxicity of CCl4 from that ingested in water.