Pr. Mayer, ABSORPTION, METABOLISM, AND OTHER FACTORS THAT INFLUENCE DRUG EXPOSURE IN TOXICOLOGY STUDIES, Toxicologic pathology, 23(2), 1995, pp. 165-169
Drug exposure in toxicology studies is dependent on input from the dru
g delivery system and elimination of the drug once absorbed. Although
seemingly straightforward, absorption, metabolism, and other factors r
equire 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 transf
er, or intrinsic drug solubility limits may lead to a plateau in syste
mic plasma concentrations. Different vehicles or administration of dru
g 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 s
election 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 con
centrations. Other factors, such as age, gender, and dosing interval n
eed to be considered when interpreting toxicology studies.