PNNL

Abstract

The metabolic series (family) approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. An initial physiologically-based pharmacokinetic (PBPK) model was developed to support the implementation of the metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol, and n-butyric acid (the butyl series) (Barton et al. 2000). In conjunction with pilot pharmacokinetic studies, the model was used to design the definitive intravenous (i.v.) PK studies. Rats were implanted with dual indwelling cannulae and administered test compounds by i.v. bolus dose, i.v. 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 from these experiments. The respiratory bioavailability of n-butyl acetate and n-butanol was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following i.v. administration, and inhalation exposure to n-butyl acetate and n-butanol. A fully scaled human version of the model successfully reproduces arterial blood n-butanol kinetics following inhalation exposure to n-butanol. These validated i.v (rat) and inhalation route models (rat, butyl acetate, n-butanol; human, butanol only) can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Further, this work demonstrates the usefulness of i.v. kinetic data for parameterization of systemic metabolism and the value of collaboration between experimentalists and kineticists in the development of PBPK models. The product of this effort, validated rat and human PBPK models for the butyl series compounds, illustrates the effectiveness of broad multi-institutional public/private collaborations in the pursuit of developing state of the art tools for risk assessment. (250 words) Keywords: PBPK model, Pharmacokinetics, Acetates, Extrapolation, Risk Assessment, Metabolic Series Approach, n-Butyl Acetate, n-Butanol, n-Butyric Acid