Development of a physiologically based pharmacokinetic model for hydroquinone

Hydroquinone (HQ) produces nephrotoxicity and renal tubular adenomas in mal e F344 rats following 2 years of oral dosing. Female F344 and SD rats are c omparatively resistant to these effects. Nephrotoxicity and tumorigenicity have been associated with a minor glutathione conjugation pathway following the oxidation of HQ to benzoquinone (BQ), The majority of administered dos es (90-99%) consists of glucuronide and sulfate conjugates of HQ. An initia l physiologically based pharmacokinetic model was developed to characterize the role of kinetics in the strain differences observed in HQ-induced rena l toxicity and tumorigenicity. Partition coefficients, protein-binding, and metabolic rate constants were determined directly or estimated from a seri es of in vivo and in vitro studies. Metabolism was confined to the liver an d GI tract, The total flux through the glutathione pathway represented the "internal dose" of HQ for nephrotoxicity. Simulations were compared to a va riety of data from male and female F344 rats, male SD rats, and a single ma le human volunteer. Simulations of intraperitoneal administration resulted in higher amounts of glutathione conjugates than comparable oral doses. Thi s was consistent with protein-binding and toxicity studies and emphasized t he importance of first-pass GI tract metabolism. In addition, male F344 rat s were predicted to form more total glutathione conjugates than SD rats at equivalent dose levels, which was also consistent with the observed strain differences in renal toxicity, This model represents the first stage in the development of a biologically based dose-response model for improving the scientific basis for human health risk assessments of HQ. (C) 2000 Academic Press.