Journal Article

Development of a Physiologically Based Pharmacokinetic Model of Isopropanol and Its Metabolite Acetone

Harvey J. Clewell, P. Robinan Gentry, Jeffery M. Gearhart, Tammie R. Covington, Marcy I. Banton and Melvin E. Andersen

in Toxicological Sciences

Volume 63, issue 2, pages 160-172
Published in print October 2001 | ISSN: 1096-6080
Published online October 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/63.2.160
Development of a Physiologically Based Pharmacokinetic Model of Isopropanol and Its Metabolite Acetone

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A physiologically based pharmacokinetic (PBPK) model for isopropanol (IPA) and its major metabolite, acetone, is described. The structure of the parent chemical model, which can be used for either IPA or acetone by choosing the appropriate chemical-specific parameters, is similar to previously published models of volatile organic chemicals such as styrene. However, in order to properly simulate data on the exhalation of IPA and acetone during inhalation exposures, it was necessary to expand the description of the lung compartment to include a subcompartment for the upper respiratory tract mucus layer. This elaboration is consistent with published PBPK models of other water-soluble vapors in which the mucus layer serves to absorb the chemical during inhalation and then release it during exhalation. In the case of IPA exposure, a similar PBPK structure is used to describe the kinetics of the acetone produced from the metabolism of IPA. The resulting model is able to provide a coherent description of IPA and acetone kinetics in the rat and human for exposures to IPA by several routes: intravenous, intraperitoneal, oral, inhalation, and dermal. It is also able to consistently reproduce kinetic data for exposures of rats or humans to acetone. Thus, the model provides a validated framework for performing chemical-specific route-to-route extrapolation and cross-species dosimetry, which can be used in place of generic default calculations in support of risk assessments for IPA and acetone.

Keywords: PBPK model; isopropanol; CAS# 67-63-0; acetone; CAS# 67-64-1

Journal Article.  7884 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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