Toxicokinetics enzyme induction

The study of absorption, distribution, metabolism and excretion in toxicology studies, usually referred to as toxicokinetics, provides extremely useful information on the pharmacokinetics of high doses and of repeated doses of the compound. The dose dependency of the pharmacokinetics and the possible time effects, e.g. a decrease in exposure over time as a result of enzyme induction, is essential information for the interpretation of the toxicity findings as well as for the planned clinical studies. 

Heinrich-Hirsch B, Beck H, Chahoud 1, et al. 1997. Tissue distribution, toxicokinetics and induction of hepatic drug metabolizing enzymes in male rats after a single s.c. dose of 3,4,3, 4 -tetrachlorobiphenyl (PCB-77). Chemosphere 34(5-7) 1523-1534. 

Nonlinearity in toxicokinetics can be assessed by comparing relevant parameters, e.g., AUC, after different dose levels, or after single and repeated exposure. Dose dependency may be indicative of saturation of enzymes involved in the metabolism of the compound. An increase of AUC after repeated exposure as compared to single exposure may be an indication for inhibition of metabolism. A decrease in AUC may be an indication for induction of metabohsm. 

In animal studies acetone has been found to potentiate the toxicity of other solvents by altering their metabolism through induction of microsomal enzymes, particularly cytochrome P-450. Reported effects include enhancement of the ethanol-induced loss of righting reflex in mice by reduction of the elimination rate of ethanol increased hepatotoxicity of compounds such as carbon tetrachloride and trichloroethylene in the rat potentiation of acrylonitrile toxicity by altering the rate at which it is metabolized to cyanide and potentiation of the neurotoxicity of -hexane by altering the toxicokinetics of its 2,4-hexane-dione metabolite.Because occupationally exposed workers are most often exposed to a mixmre of solvents, use of the rule of additivity may underestimate the effect of combined exposures. ... 

Induction [55,56] Enzyme activity increases with all potential toxicokinetic (and ultimately toxicodynamic) consequences Competent cultured human cells receptor binding-based assays available and nuclear receptor activation assays (even HTS) Need of (induction-competent) cells for functional studies overestimation of induction potential due to high drug concentrations in nuclear receptor assays... 

With over 200 hydrocarbons present in JP-8, there is the possibility of toxicokinetics- and toxicodynamics-related antagonistic, additive, and synergistic interactions among various hydrocarbon components. The toxicokinetic parameters of individual chemicals in a complex mixture such as JP-8 are very different from the toxicokinetic profiles of individual chemicals. Chemical-chemical interactions may be related to mutual induction of competing metabolic and elimination pathways or mutual inhibition of absorption, distribution, metabolism, and excretion. Similar CYP450 enzymes and phase II conju-gative metabolic pathways metabolize many alkane hydrocarbons (NRC1996). 

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