The general aim of the proposed research is to investigate the influence of disease on the relationship between the concentration and intensity of pharmacologic effects of drugs. The studies will be designed to differentiate between the direct effects of diseases on the biophasic drug concentration-pharmacologic response relationship (which will be of primary interest) on the one hand, and indirect (and therefore potentially confounding) effects on the other. The indirect effects, which will be either excluded or accounted for in our research strategy, include pharmacokinetic perturbations such as disease-induced changes in protein binding, distribution, metabolism and excretion, formation and elimination of active metabolites, drug-drug metabolite interactions, and differential pharmacologic activities of individual enantiomers. We will use animal models of disease, specifically rats with experimental renal failure, hepatic dysfunction diabetes, thyroid dysfunction, hyperpyrexia, and arthritis. We will also investigate the effects of certain nonpathologic changes in physiologic status, particularly pregnancy and possibly obesity. The drugs to be studied represent examples of CNS depressants (phenobarbital), anticonvulsants (phenytoin), analgesics (acetaminophen), and antihypertensives (clonidine). The pharmacologic effects to be measured include onset of loss of righting reflex, protection from seizures, analgesia, and changes of blood pressure. Two different experimental models of each disease will be utilized to distinguish effects referable to a particular method of inducing the disease from effects characteristic of the disease itself. The roles of potentially active or interactive metabolites will be assessed directy. The longer term objective of this research is to address a question that is central to the individualized optimization of patients' drug therapy: will certain diseases or other alterations of physiologic status modify not only the pharmacokinetics but also (and perhaps predominantly) the pharmacodynamics (concentration-effect relationship) of a drug?
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