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

A mechanism-based dosimetry model was developed to describe2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal 2u-globulin(2u) nephropathy in the male Fischer 344 rat. Experimental datawere collected to estimate the chemical-specific parameters(metabolic constants, tissue solubility, and oral absorptionrate) necessary to describe TMP-2-OH dosimetry in male rats.The concentrations of 2u and TMP-2-OH were measured in malerats 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 behaviorof TMP-2-OH and 2u in the kidney, but overestimated their renalconcentrations by two or threefold. Simulations of renal 2uconcentration were sensitive to changes in TMP-2-OH-2u-bindingaffinity and degradation rate of the TMP-2-OH-protein complex.In contrast, simulation of the concentration of TMP-2-OH inthe kidney was most sensitive to the amount of protein present.Oral absorption of TMP-2-OH was dose dependent. The model predictedthat 2u and TMP-2-OH concentration in the kidney is sensitiveto changes in the rate of TMP-2-OH absorbed after oral administration.This model permitted a more rigorous evaluation than has previouslybeen possible of the combination of protein characteristicsand chemical dosimetry required for the accumulation of 2u inthe kidney of male rats. The behavior of the model is consistentwith the qualitative aspects of the 2u hypothesis. However,further characterization of 2u distribution and renal hydrolysiswill be required in order to fully characterize the hypothesisat the quantitative level.