Physiologically based pharmacokinetic model for vinylidene chloride.

Area of Science:

• Toxicology
• Pharmacokinetics
• Biochemistry

Background:

• Vinylidene chloride (VDC) is a hepatotoxin and suspected carcinogen.
• VDC toxicity is mediated by reactive metabolites.
• Glutathione (GSH) status influences VDC toxicity.

Purpose of the Study:

• To develop a physiologically based pharmacokinetic (PB-PK) model for VDC in rats.
• To elucidate the relationship between VDC absorption, metabolism, and GSH detoxification.
• To simulate VDC kinetics and toxicity.

Main Methods:

• Development of a PB-PK model for VDC.
• Incorporation of VDC oxidative metabolism and GSH conjugation.
• Simulation of VDC concentrations and GSH levels.

Main Results:

• The PB-PK model accurately predicts VDC concentrations in blood, tissues, and exhaled air.
• The model successfully predicts liver GSH levels.
• The model explains complex VDC dose-response mortality curves.
• VDC metabolism is sensitive to absorption rate due to its low blood:air partition coefficient and saturable metabolism.
• Blood VDC half-life is influenced by fat reequilibration, not solely metabolism.

Conclusions:

• PB-PK modeling is a powerful tool for understanding VDC toxicokinetics.
• The model provides insight into factors regulating VDC toxicity.
• The model accurately simulates VDC behavior under various experimental conditions.