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Physiologically-based pharmacokinetic (PBPK) modeling of metabolic pathways of bromochloromethane
Citation:
Cuello, W., J. Simpson, M. Sawyer, M. V. EVANS, M. Sawyer, AND C. R. EKLUND. Physiologically-based pharmacokinetic (PBPK) modeling of metabolic pathways of bromochloromethane. Presented at Research Experience for Undergraduates (REU) Meeting, NC STATE UNIVERSITY, Raleigh, NC, May 31 - August 04, 2011.
Impact/Purpose:
Application of PBPK modeling to test different metabolic hypotheses
Description:
Bromochloromethane (BCM) is a volatile compound that if metabolized can lead to toxicity in different organs. Using a physiologically-based phannacokinetic model, we explore two hypotheses describing the metabolic pathways of BCM in rats: a two-pathway model exploiting both the enzyme CYP2El and the enzyme glutathione transferase (GST) for metabolism, and a two-binding site model where metabolism can occur at a hypothesized second binding site on CYP2E1. After optimizing for the parameters needed in each model, our findings show that both variations of the metabolic pathway models generate curves that fit our data well; however, the two-binding site model more accurately fits the data obtained at higher concentrations of BCM when using least squares regression to compare metabolic models. In addition, we explored the sensitivity of different parameters for each model using our obtained optimized values as well as forregions around these values. (This abstract does not reflect EPA policy).