Physiologically based pharmacokinetic model for vinylidene chloride.
Vinylidene chloride (VDC), a potent hepatotoxin and suspected carcinogen, is metabolized by mixed-function oxidases into a reactive metabolite(s) which is responsible for its toxicity. The metabolite is detoxified by glutathione (GSH), and liver GSH status is an important factor in the expression of VDC toxicity. A physiologically based pharmacokinetic (PB-PK) model has been developed for VDC in the rat based on oxidative metabolism of VDC and subsequent GSH detoxification of metabolite. The model offers insight into the complex interrelationship between the processes of absorption, metabolism, and GSH conjugation, and simulates the manner in which these factors operate in regulating VDC toxicity. The PB-PK model successfully predicts blood, tissue, and exhaled air concentrations of VDC, and liver GSH levels as a function of dose and route of administration. The model also explains the complex dose-response mortality curves seen with VDC. Because of the low blood:air partition coefficient of VDC and its saturable metabolism, the amount of VDC dose that is metabolized is sensitive to the rate of absorption. After an intravenous bolus dose, most of the administered VDC is exhaled unchanged within a few minutes. Blood VDC half-life is not representative of metabolism rates but to reequilibration of VDC from fat. Rats with greater fat content, therefore, display longer VDC blood half-lives. Simulations are shown to demonstrate the strength of PB-PK modeling techniques in understanding the kinetic behavior of VDC in the rat under a variety of experimental conditions.
D'Souza
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Proctor & Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio 45239-8707.
Andersen
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D000273:Adipose Tissue / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D004000:Dichloroethylenes / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D014018:Tissue Distribution
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; C029297:vinylidene chloride; D006899:Mixed Function Oxygenases; D005978:Glutathione