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PHARMACOKINETICS OF N-BUTYL ACETATE AND ITS METABOLITES IN MALE SPRAGUE DAWLEY RATS AFTER INTRAVENOUS ADMINISTRATION
Citation:
Deisinger, P. J., J. Teeguarden, H Barton, J. C. English, W. D. Faber, T. R. Tyler, AND M. I. Blanton. PHARMACOKINETICS OF N-BUTYL ACETATE AND ITS METABOLITES IN MALE SPRAGUE DAWLEY RATS AFTER INTRAVENOUS ADMINISTRATION. Presented at SOT, San Francisco, CA, March 25-29, 2001.
Description:
FAMILY APPROACH PBPK MODELING OF N-BUTYL ACETATE AND ITS METABOLITES IN MALE RATS
P.J. Deisinger1, J.G. Teeguarden2, H.A. Barton3, J.C. English1, W.D. Faber4, T.R. Tyler5, M.I. Banton6, M.E. Andersen7. 1Health & Environ. Laboratories., Eastman Kodak Company, Rochester, NY, USA. 2K.S. Crump Group, ICF Consulting, RTP, NC, USA. 3ETD, NHEERL, ORD, USEPA, RTP, NC, USA. 4WFTC, LLC, Victor, NY, USA. 5Health & Environ. Affairs Dept., Union Carbide Corp., Danbury, CT, USA. 6Toxicology, Health, Safety & Environ., Shell Chemical Co., Houston, TX, USA. 7Dept. of Environ. Health, Colorado State U, Fort Collins, CO, USA
The family approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic data for each compound and toxicity data for the parent compound. An initial PBPK model was developed to support the implementation of the family approach for n-butyl acetate and its subsequent metabolites, n-butanol, and butyric acid (the butyl series) (Barton et al., 1999). The objective of this work was to refine the PBPK model for the butyl series based on IV kinetic data collected in male Sprague-Dawley rats. An iterative process using the PBPK model and pilot experiments guided development of the definitive PK studies. Rats were implanted with dual indwelling cannulae and administered test compounds by IV bolus dose or infusion. Concentrations of n-butyl acetate and metabolites in whole blood were assayed by GC/MS-SIM. Hepatic and extra hepatic kinetic constants (Vmax, Km) for metabolism were estimated by fitting the model to the blood time course data. Simulations of blood concentration time course data indicated significant extra hepatic metabolism of butanol and butyric acid. The resulting parameterization of the butyl series PBPK model successfully reproduces the blood time course of these compounds following bolus IV administration and IV infusion (butyric acid). This work demonstrates the usefulness of IV kinetic data for parameterizing systemic metabolism and the value of initial PBPK models for guiding the collection of appropriate experimental data. (Abstract does not reflect EPA policy.).