The objective is to investigate the contribution of concurrent drug administration and coexisting disease states to the variability in response to drugs. Specific protocols utilize pharmacokinetic approaches to investigate the mechanism(s), magnitude and clinical relevance of these factors. During the proposed award period, work will focus on the area of inhibition of hepatic drug clearance by two classes of compounds: interferon and antifungal imidazoles, such as ketoconazole. Human studies will be directed at studying the time course, magnitude and specificity of inhibition by these two drug classes, which may also provide insight as to the mechanism of, and possible differences in, inhibition by these two classes. Most protocols involve patients who will be receiving interferons or ketoconazole as part of ongoing treatment regimens. The human protocols will be supplemented by animal experiments (primarily in mice) which will allow more extensive dose-response and time-course relationships to be established. We will also begin to establish in vitro, biochemical approaches in this laboratory directed at understanding the mechanism and specificity of these inhibition interactions. Because of the likely future use of interferons and ketoconazole in cancer, viral or fungal infections and immunodeficiency syndromes as part of combination drug therapy, it is particularly important to understand possible differences between interferons and possible specificity in inhibition of hepatic metabolism.
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