Effect of overloading pathways on toxicity

Overloading of metabolic pathways results in a disproportionate relationship between the concentration of drug and/or metabolites and dosage. As a result, both the degree and type of toxicity may be affected. Metabolic pathways which may be overloaded include transport, drug or metabolite binding, enzymatic transformations of drug or metabolites and systems utilizing conjugating cofactors. Examples in which the degree of toxicity is affected by overloading the transport and distribution system or by overloading conjugation mechanisms or by overloading plasma and tissue binding capacities will be discussed. These include the acute toxicity of streptomycin, chronic toxicity of some nitrofurans and toxic effects of bromobenzene and warfarin. The effect of route of administration on the degree of toxicity of Cambendazole for laboratory and target animals will be discussed. Overloading enzymatic transformation of drug and/or metabolites results in disproportionate changes in the blood and tissue levels and relative quantities of drug and metabolites. This may affect the type of toxicity observed when the drug is administered by differing routes or methods. An example of this phenomenon may be the chronic toxicity in rats given FANFT in the diet or dosed by gavage. The relevance of these toxicity effects in considering the human hazard of tissue residues of animal health products will be discussed.