Immunosuppressants, such as cyclosporine, are widely administered to transplant patients to prevent organ rejection. The clinical use of cyclosporine is hampered by significant toxicity to the CNS, liver and kidney. While these toxicities are related to circulating cyclosporine concentrations, they are not always predictable. Although dosing regimens exist, large inter- and intra-patient variability in pharmacokinetic parameters may complicate predicting therapeutic cyclosporine blood concentrations. The toxicity may be related to changes in hepatic or intestinal drug metabolism. Cyclosporine is known to alter its own hepatic metabolism which may be responsible for the large variability in clinical responses. The objective of the proposal is to investigate possible mechansims of immunosuppressant-induced alterations in drug metabolism, using cyclosporine as the prototype drug. The hypothesis being tested is that chronic immunosuppressive therapy causes a modulation in pituitary function leading to altered circulating levels of growth hormone and prolactin which results in decreased drug metabolism. In addition, chronic immunosuppressive therapy causes an increase in circulating transforming growth factor Beta-1 or TGF Beta-1 which results in suppressed drug metabolism. These changes, alone or in concert with one another, may explain the changes in drug metabolism seen previously with immunosuppressive therapy. In order to investigate the role of growth hormone, rats will be administered cyclosporine along with growth hormone. These studies will determine the role of growth hormone and whether or not cyclosporine changes growth hormone levels. Next the proposed studies will examine the role of prolactin. Along with cyclosporine, rats will be administered exogenous prolactin or a prolactin antagonist to determine the effects of cyclosporine on the circulating levels of this pituitary hormone. Finally, rats will be given cyclosporine and TGF beta1 to determine whether or not this cytokine has a significant role in immunosuppressant-induced changes in drug metabolism. These studies will provide information how cyclosporin and other immunosuppressive drugs may regulate hepatic and intestinal drug metabolism. This information will have direct application to transplant patients and give clinicians needed information regarding the relationship between immunosuppressive therapy and the prediction of toxicity.
