Understanding the metabolism, distribution, and elimination of chemical xenobiotics is often critical to an appreciation of their toxic effects. Extrapolation of results from animal testing to possible human health effects requires knowledge of metabolic pathways and of in vivo kinetic behavior. Investigation of mechanistic aspects of metabolic processes allows greater understanding of how metabolism of a xenobiotic might lead either to detoxification or to a reactive metabolite with greater toxicity. As more is learned about mechanisms of metabolism, more accurate predictions of possible metabolic pathways for new compounds should be possible. This group carried out studies on oxazepam (OXM), tris(2- chloroethyl) phosphate (TRCP), and ethoxyquin (EQN) in the past year. In an NTP study OXM, a Valium analog, has been found to increase the incidence of liver tumors in mice. Induction of OXM metabolism by pretreatment with OXM results in increased glucuronidation and a shift from fecal to urinary elimination. This altered elimination pattern closely resembles that found in man. Pharmacokinetics of TRCP, a flame retardant, were investigated in anesthetized male rats using conventional jugular vein cannulation and microdialysis coupled with mass spectrometry. All pharmacokinetic parameters determined were significantly different for the two methods at the p=0.05 level. The antioxidant EQN was rapidly absorbed, metabolized and excreted in urine as sulfate or glucuronide conjugates following oral administration to either rats of mice. Bile contained three glutathione conjugates.
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