The goal of this unit is to define and characterize the pharmacokinetics and metabolism of immunosuppressive agents and to develop and characterize measures of immunosuppressive activity which can be correlated with the pharmacokinetics of immunoregulating agents with particular emphasis on cyclosporine, FK506 and prednisone/prednisolone. these highly potent, as well as potentially toxic, drugs are frequently concentration monitored in transplant patients, yet with little apparent success in improving the therapeutic outcome. We hypothesize that studies which quantitate the relationship between drug concentrations, as well as specific measures of metabolites, with immunologic measures reflecting an organ site of action, such as in liver biopsies, can lead to a rational understanding of the potential for a relevant pharmacokinetic/pharmacodynamic correlation. We further hypothesize that an understanding of the enzymatic processes involved, will lead to a rational explanation for the multiple drug interactions found with the immunosuppressive agents. We specifically plan to a) characterize the pharmacokinetics and metabolic aspects of immunosuppressive agents and b) characterize the effect of immunosuppressive agents on cytokine (IL-2, IL-4, IL-5, IL-10 and IFN- gamma) gene expression and production. In the studies to be undertaken we plan to characterize the P-450 isozymes responsible for metabolism of cyclosporine and FK506 in male and female rat subcellular hepatic and intestinal fractions, in vivo and in vitro, and the effects of a series of inducers; determine the in vivo pharmacokinetics of cyclosporine and FK506 in control rats and rats induced with selected drugs; in control and liver transplanted rats, determine the hepatic biopsy and corresponding systemic concentrations of cyclosporine and FK506 and their metabolites; in health volunteers following oral and intravenous dosing of cyclosporine characterize the effect of inducers such as ethinyl estradiol, rifampin and conjugated estrogens; quantitate the concentrations of cyclosporine and FK506 and their metabolites in liver biopsies and in the systemic circulation from liver transplant patients, as well as characterize in these biopsies the liver P-450s and the cytokine gene expression and production. Studies will also: evaluate and analyze the cytokine gene expression and production by human lymphocytes in response to allogeneic hepatic cells cultures in the presence of cyclosporine and FK506 and their metabolites; examine the potential correlation of the intragraft cytokine transcripts with intragraft and systemic concentrations of immunosuppressive agents; and examine the potential correlation or lack of correlation between the intragraft cytokine profile and the cytokine profile generated in vitro using patients' lymphocytes and donor alloantigen.
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