A physiological model for ligand-induced accumulation of alpha(2u) globulin in male rat kidney - Roles of protein synthesis and lysosomal degradationin the renal dosimetry of 2,4,4-trimethyl-2-pentanol

A physiologically based pharmacokinetic (PBPK) model was constructed for th e disposition of 2,4,4-trimethyl-2-pentanol (TMP-2-OH) in male rats and its induction of accumulation of renal alpha(2u)-globulin (alpha 2u). The mode l included diffusion-restricted delivery of TMP-2-OH to compartments repres enting liver, lung, fat, kidney, GI tract, aggregated rapidly perfused tiss ues, and aggregated slowly perfused tissues. Metabolism by oxidation and gl ucuronidation was included for liver and kidneys. Rates of hepatic alpha 2u production and resorption by renal proximal tubules were taken from the li terature. Degradation of liganded alpha 2u by renal lysosomal cathepsins wa s modeled with a K-m value corresponding to the measured 30% reduction in p roteolytic efficiency and with free and bound forms of alpha 2u competing f or access to the enzymes. Increased pinocytotic uptake of alpha 2u into the kidney induces cathepsin activity. A model that ascribed renal alpha 2u ac cumulation solely to reduced lysosomal proteolysis failed to reproduce the observed accumulation. The model could reproduce experimental observations if a transient increase in hepatic synthesis of alpha 2u, stimulated by the presence of liganded alpha 2u in the blood, and accelerated secretion of t he protein from the liver were assumed. This model reproduces time course d ata of blood and kidney TMP-2-OH and renal alpha 2u concentrations, suggest ing that renal accumulation of alpha 2u is not simply a consequence of redu ced proteolytic degradation but may also involve a transient increase in he patic alpha 2u production. The model predicts increased delivery of TMP-2-O H to the kidney and consequent increased renal production of potentially to xic TMP-2-OH metabolites than would be the case if no alpha 2u were present . Induced lysosomal activity and increased production of toxic metabolites may both contribute to the nephrotoxicity observed in male rats exposed to an alpha 2u ligand or its precursor. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.