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A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR INTRAVENOUS AND INHALATION-ROUTE PHARMACOKINETICS OF BUTYL ACETATE AND METABOLITES N-BUTANOL AND N-BUTYRIC ACID
Citation:
Teeguarden, J., P. J. Deisinger, T. S. Poet, J. C. English, W. D. Faber, R. A. Corley, H A. Barton, AND H. J. Clewell. A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR INTRAVENOUS AND INHALATION-ROUTE PHARMACOKINETICS OF BUTYL ACETATE AND METABOLITES N-BUTANOL AND N-BUTYRIC ACID. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Risk assessment for n-butyl acetate and metabolites n-butanol and n-butyric acid (the butyl series) can be accomplished with limited toxicity data and pharmacokinetic data for each compound through application of the "family approach" (Barton et al., 2000). The necessary quantitative and interpretive tool is a PBPK model describing the inhalation-route blood kinetics of the series members. A series of revisions of the initial model were carried through to validation of the inhalation route (BA and BOOH) for male SD rats. Rats were implanted with dual indwelling cannulae and administered BA, BOH or BOOH by IV bolus dose, IV infusion or by inhalation in a recirculating closed chamber. Hepatic, vascular and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data. The respiratory bioavailability of BA (100%) and BOH (~50%) was estimated from a novel closed chamber inhalation study design (Poet, 2002) involving simultaneous measurement of ventilation rates, chamber loss (uptake) and blood kinetics. The resulting PBPK model successfully reproduces the blood time course of these compounds following inhalation exposure to BA and BOH, verifying the description of the blood kinetics based on i.v. studies. This effort highlights the value of new, cost effective dosimetry based approaches to risk assessment for metabolically related compounds. (This abstract does not represent EPA policy).