PMID: 7541379Apr 1, 1995Paper

Development of a mechanism-based dosimetry model for 2,4,4-trimethyl-2-pentanol-induced alpha 2u-globulin nephropathy in male Fischer 344 rats

Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology
S BorghoffR B Conolly

Abstract

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...Continue Reading

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