Development of a physiologically based pharmacokinetic model for hydroquinone

Area of Science:

• Toxicology
• Pharmacokinetics
• Risk Assessment

Background:

• Hydroquinone (HQ) induces nephrotoxicity and renal tubular adenomas in male F344 rats.
• Female rats and Sprague-Dawley (SD) rats exhibit resistance to HQ's toxic effects.
• Toxicity is linked to a minor glutathione conjugation pathway of HQ oxidation to benzoquinone (BQ).

Purpose of the Study:

• To develop a physiologically based pharmacokinetic (PBPK) model for hydroquinone (HQ).
• To characterize kinetic factors influencing strain differences in HQ-induced renal toxicity and tumorigenicity.
• To provide a basis for improving human health risk assessments of HQ.

Main Methods:

• In vivo and in vitro studies to determine partition coefficients, protein-binding, and metabolic rate constants.
• Development of an initial PBPK model for HQ.
• Simulations compared with data from male/female F344 rats, male SD rats, and a human volunteer.

Main Results:

• Metabolism of HQ occurs in the liver and GI tract; 90-99% are glucuronide/sulfate conjugates.
• Glutathione pathway flux represents the internal dose for nephrotoxicity.
• Simulations indicated higher glutathione conjugates with intraperitoneal vs. oral dosing, highlighting GI tract first-pass metabolism.
• Male F344 rats predicted to form more glutathione conjugates than SD rats, aligning with observed toxicity differences.

Conclusions:

• The PBPK model successfully characterized kinetic factors in HQ-induced renal toxicity.
• First-pass GI tract metabolism significantly influences HQ's toxicological profile.
• The model supports observed strain differences in HQ toxicity and is a step towards biologically based dose-response modeling for risk assessment.