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© 1995 Oxford University Press

research-article

Development of a Mechanism-Based Dosimetry Model for 2,4,4-Trimethyl-2-pentanol-lnduced {alpha}2u-Globulin Nephropathy in Male Fischer 344 Rats

SUSAN J. BORGHOFF1, MICHAEL L. GARGAS2, MELVIN E. ANDERSEN3 and RORY B. CONOLLY

Chemical Industry Institute of Toxicology 6 Davis Drive, P.O. Box 12137, Research Triangle Park, North Carolina 27709

Received February 3, 1994; accepted August 24, 1994

A mechanism-based dosimetry model was developed to describe 2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal {alpha}2u-globulin ({alpha}2u) nephropathy in the male Fischer 344 rat. Experimental data were collected to estimate the chemical-specific parameters (metabolic constants, tissue solubility, and oral absorption rate) necessary to describe TMP-2-OH dosimetry in male rats. The concentrations of {alpha}2u and TMP-2-OH were measured in male rats up to 64 hr after a single oral dose of TMP-2-OH (6, 60, or 600 mg/kg). The model predicted the time course behavior of TMP-2-OH and {alpha}2u in the kidney, but overestimated their renal concentrations by two or threefold. Simulations of renal {alpha}2u concentration were sensitive to changes in TMP-2-OH-{alpha}2u-binding affinity and degradation rate of the TMP-2-OH-protein complex. In contrast, simulation of the concentration of TMP-2-OH in the kidney was most sensitive to the amount of protein present. Oral absorption of TMP-2-OH was dose dependent. The model predicted that {alpha}2u and TMP-2-OH concentration in the kidney is sensitive to changes in the rate of TMP-2-OH absorbed after oral administration. This model permitted a more rigorous evaluation than has previously been possible of the combination of protein characteristics and chemical dosimetry required for the accumulation of {alpha}2u in the kidney of male rats. The behavior of the model is consistent with the qualitative aspects of the {alpha}2u hypothesis. However, further characterization of {alpha}2u distribution and renal hydrolysis will be required in order to fully characterize the hypothesis at the quantitative level.


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