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ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING
Citation:
Linskey, C. F., R. A. Harrison, G. Zhao, H A. Barton, J. C. Lipscomb, AND M V. Evans. ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING. Presented at SOT, San Francisco, CA, March 25 - 29, 2001.
Description:
ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING
Linskey, C.F.1, Harrison, R.A.2., Zhao, G.3., Barton, H.A., Lipscomb, J.C4., and Evans, M.V2., 1UNC, ESE, Chapel Hill, NC ; 2USEPA, ORD, NHEERL, RTP, NC; 3 UNC, Curriculum in Toxicology, Chapel Hill, NC; 4USEPA, ORD, NCEA, Cincinnati, OH.
Chloroform is a major byproduct of water disinfection by chlorine addition and a known hepatotoxicant. The goals of this project were:1) to generate in vitro metabolism data for rat liver microsomes using chloroform and 2) to combine experimentation with modeling to estimate the Michaelis-Menten metabolic constants, Vmax and Km. The in vitro experiments included duplicate test vials and a control vial for each run repeated at multiple initial chloroform concentrations of 5, 10, 20, and 50 mM applied in the microsomal compartment. Sequential gas chromatographic sampling from the headspace provided a time course description of the decline observed due to metabolism. Analysis and subsequent modeling of the experimental data were done with a two-compartment model including the headspace and microsomal compartments. In the model, chemical loss due to glass adsorption was assumed to be zero after estimation using control microsomal preparations. Subsequently, mass conservation equations were written to describe partitioning and the metabolism occurring in the microsomal suspension. Metabolic parameters were estimated from the experimental data to obtain the average maximum metabolic rate in the rat microsomes. Preliminary modeling results estimated Vmax at 0.043 mg/min and Km at 10 mg/liter. Future experiments will estimate metabolic rates for chloroform by human microsomes. An accurate assessment of hepatic microsomal metabolism of chloroform by rats is important when extrapolating metabolic parameters from rodent data to humans. In summary, the combination of experimental in vitro kinetic data with modeling provides an opportunity for the estimation of metabolic constants in different species. (This abstract does not reflect EPA policy).