Preliminary studies showed that copper (Cu) deficiency in the rat significantly enhanced: i) antiinflammatory activity of aspirin and cortisol; ii) hypnotic activity of pentobarbital; and iii) cocaine-induced seizures and mortality. A review of the literature revealed only few articles where such effects were reported. Several reports, however, did indicate INDIRECTLY that such alterations were indeed likely. Nevertheless, it was clear that among many types of interactions that can alter the activity of a drug, this type of drug-nutritional state interaction has not been well studies. We, therefore, propose to study it with respect to Cu deficiency. These studies may shed some light, for example, on the observed wide variation in susceptibility of humans to cocaine- induced arrhythmias and death, and may illustrate the importance of the assessment of nutritional status with respect to minerals especially during therapy with agents with a narrow therapeutic window. The overall aim of this proposal is to study the pharmacodynamic, pharmacokinetic, and metabolic basis for the effects of Cu deficiency on aspirin, cortisol, and cocaine activities in the Cu- deficient (CUD) rat by: i) comparing the antiinflammatory activity of aspirin in CUD and Cu-sufficient (CUS) rats at 4 stages of Cu deficiency, ii) comparing the analgesic activity of aspirin in CUD and CUS rats; iii) studying the reversibility of the effects of Cu deficiency on aspirin; iv) by comparing dose response curves of aspirin, cortisol, and cocaine in CUD and CUS rats; v) comparing pharmacokinetics and hepatic metabolism of aspirin, cortisol, and cocaine in CUD and CUS rats; and by vi) correlating various effects of Cu deficiency with changes in the degree of Cu deficiency and formulating a hypothesis for the mechanism by which Cu deficiency exerts its effects. Our long term goal is to study the significance of mineral deficiencies in altering the activity of drugs with a narrow therapeutic window because it is with these drugs that minor changes in activity may lead to major undesirable consequences.
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