Abstract
Development of a Mechanism-Based Dosimetry Model for 2,4,4-Trimethyl-2-pentanol-Induced α2u-Globulin Nephropathy in Male Fischer 344 Rats. Borghoff, S. J., Gargas, M. L., Andersen, M. E., and Conolly, R. B. (1995). Fundam. Appl. Toxicol. 25, 124-137. A mechanism-based dosimetry model was developed to describe 2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal α2u-globulin (α2u) 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 α2u 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 α2u in the kidney, but overestimated their renal concentrations by two or threefold. Simulations of renal α2u concentration were sensitive to changes in TMP-2-OH-α2u-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 α2u 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 α2u in the kidney of male rats. The behavior of the model is consistent with the qualitative aspects of the α2u hypothesis. However, further characterization of α2u distribution and renal hydrolysis will be required in order to fully characterize the hypothesis at the quantitative level.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call