Interspecies comparisons in toxicology: the utility and futility of plasma concentrations of the test substance.
A classical dilemma in toxicology is how the dose administered relates to the dose delivered to the target site. Plasma concentrations of the test substance may be misleading since the concentration of any given substance in the plasma may not be representative of its concentration in tissues. Furthermore, a given tissue concentration of a xenobiotic can evoke responses which are highly species-dependent. While evaluating toxicity data within one species, plasma concentrations reflect the effects of route of administration, bioavailability, dose level, multiple dosing, age, gender, etc. However, when toxicity data is compared across species, the relevance of plasma concentrations depends on the nature of the toxicity. Reversible, pharmacodynamic effects often correlate with plasma concentrations, although there may be marked interspecies differences in dose-response relationships. Irreversible effects, if pharmacodynamic in origin, often correlate better with the intensity/duration of the pharmacodynamic response, rather than with plasma concentration. On the other hand, irreversible effects, if chemically mediated, may not correlate at all with plasma concentration, the lesions being caused by reactive metabolites of fleeting existence, which rarely survive long enough to leave their site of synthesis. They cannot be measured in the plasma nor predicted from plasma concentrations of the parent xenobiotic. The limitations of plasma concentrations in interpreting the toxicology of substances which are tissue-sequestered, which are subject to pharmacogenetic factors, or which show plasma concentrations that are not proportional to dose are also discussed. Mention is made of possible alternatives to plasma concentrations in assessing exposure in toxicology studies.
Monro
A M
AM
Pfizer Central Research, Groton, Connecticut 06340.
D000818:Animals; D001682:Biological Availability; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010599:Pharmacokinetics; D013045:Species Specificity; D014018:Tissue Distribution; D014116:Toxicology