PHARMACOKINETICS IN THE INTERPRETATION OF CHRONIC TOXICITY TESTS - LAST-IN, FIRST-OUT PHENOMENON

Labeled phenytoin (DPH) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (HCB) were used to experimentally test the proposed theory that the administration of a single radioactive tracer dose to control or treatment animals at the end of subacute or chronic toxicity studies can be used to determine possible self-induced change in the pharmacokinetics of the compounds. The mathematical models are based on the assumption that compartments are well stirred and that test compounds are instantaneously distributed throughout the compartments. Data from DPH experiments support the proposed theory, whereas data from the HCB experiments do not. The DPH model approximates the situation in vivo, but the accumulation of HCB in fat does not meet this criterion. It appears that HCB is accumulated and released from fat relative to the time of administration. It is suggested that individual drugs and chemicals should be tested before the proposed theory is generally applied. © 1979.