Drug-nutrient interactions and their implications for safety evaluations.
In order to assess the relevance of the drug-nutrient interactions described in this chapter to routine toxicologic studies, the range of nutrient concentrations within which these interactions may occur must be compared to the range of nutrient concentrations found in routinely used rodent diets. While obviously deficient levels of some nutrients were supplied to demonstrate some of the interactions, others occur when the nutrients are present in adequate or excess levels, such as might be found in commercially available diets. These diets are known to vary from batch to batch in nutrient content. A lifetime toxicity/carcinogenicity bioassay using rodents may last longer than 2 years, during which time several batches of diet will be used. The variation in diet composition, coupled with inadequate diet description, makes nutrient-toxin interactions not only possible, but difficult to recognize. These considerations raise the practical and philosophical question as to what type of diet is most appropriate for rodents used for safety evaluation of drugs and chemicals. Is it appropriate to use diets that vary unpredictably in nutrient content, that infer a degree of protection against chemical carcinogenesis and which supply some nutrients such as protein in great excess of dietary needs? Is the increase in sensitivity to chemical carcinogens of animals fed purified diets desirable or does this increased sensitivity of the bioassay exceed that required to assess the risk of human exposure? In other words, is the use of purified diets likely to increase the number of false positive results? Proper interpretation and extrapolation of safety evaluation studies requires adequate description of the test system. Given the profound influence of diet on the response to some toxins, the composition of the diet should, ideally, be defined with the same rigor as are the test compound and the strain, age, sex, and housing conditions of the animals. It is likely, however, that natural ingredients diets will continue to be the diets of choice in safety evaluation studies. This is largely due to economic reasons. It is possible, however, to use these diets with greater confidence if open-formula diets are used and the concentration of each nutrient is reported. Consideration should also be given to preparing diets for use in adult and aging rodents, diets in which protein content is reduced.(ABSTRACT TRUNCATED AT 400 WORDS)
D000821:Animal Feed; D000818:Animals; D000830:Animals, Laboratory / Q000502:physiology*; D001361:Avitaminosis / Q000503:physiopathology; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004044:Dietary Proteins / Q000494:pharmacology; D004347:Drug Interactions; D002149:Energy Intake; D005502:Food / Q000592:standards*; D005526:Food, Formulated; D006168:Guinea Pigs; D050356:Lipid Metabolism; D051379:Mice; D009751:Nutritional Requirements; D051381:Rats; D012377:Rodentia / Q000502:physiology*; D014131:Trace Elements / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
D004041:Dietary Fats; D004044:Dietary Proteins; D014131:Trace Elements; D014815:Vitamins