Absorption, metabolism, and other factors that influence drug exposure in toxicology studies.

Abstract

Drug exposure in toxicology studies is dependent on input from the drug delivery system and elimination of the drug once absorbed. Although seemingly straightforward, absorption, metabolism, and other factors require a more complex interpretation of plasma concentrations and the resulting area under the plasma concentration versus time curve values at doses free from significant toxicity. Absorption may be saturable due to the intestinal, physiologic processes necessary for drug transfer, or intrinsic drug solubility limits may lead to a plateau in systemic plasma concentrations. Different vehicles or administration of drug with food or in the diet may be investigated in an effort to improve systemic exposure. Metabolic profiles may be examined to aid in the selection of a toxicology species more metabolically similar to humans. This will assist in providing adequate safety margins for metabolites as well as parent compound in comparison to humans. Safety assessment of drug metabolites has taken on added significance as our knowledge of metabolite pharmacokinetics in humans has increased. Correlation of free drug concentrations, determined in protein binding studies, may provide a better correlation with toxic effects than do total drug concentrations. Other factors, such as age, gender, and dosing interval need to be considered when interpreting toxicology studies.