IMMUNOPHARMACOKINETICS AND IMMUNOPHARMACODYNAMICS

本单位的目标是定义和描述药物动力学。 和免疫抑制剂的代谢，并开发和表征 免疫抑制活性的测量可以与 免疫调节剂的药代动力学研究 环孢素、FK506和强的松/强的松龙。这些高度有效的，如 除了潜在的毒性，药物经常在 移植患者，但在改善 治疗结果。我们假设，量化的研究 药物浓度之间的关系，以及 代谢物，通过免疫措施反映器官的作用部位， 例如在肝脏活检中，可以导致对 相关药代动力学/药效学相关性的可能性。我们 进一步假设，对酶过程的理解 将导致对多种药物的合理解释 发现与免疫抑制剂的相互作用。 我们特别计划a)表征药物动力学和代谢 免疫抑制剂的方面和b)表征了 免疫抑制剂对细胞因子(IL-2、IL-4、IL-5、IL-10和干扰素-1)的影响 伽马)基因表达和生产。在即将进行的研究中，我们 计划鉴定负责新陈代谢的P-450同工酶 环孢素和FK506在雄性和雌性大鼠亚细胞肝组织中的分布 肠道部位，体内和体外，以及一系列药物的作用 诱导剂；环孢素和FK506体内药代动力学的测定 在对照组和经选定药物诱导的大鼠中；在对照组和肝脏中 移植大鼠，确定肝脏活检及相应的系统 健康人群中环孢素和FK506及其代谢物的浓度 口服和静脉注射环孢素的受试者 描述诱导剂的作用，如乙炔雌二醇、利福平和 结合雌激素；定量测定环孢素和环孢素A的浓度 FK506及其代谢物在肝活检和全身组织中的分布 来自肝移植患者的循环，以及在 这些活组织检查肝脏P-450和细胞因子基因的表达和 制作。研究还将：评估和分析细胞因子基因 人淋巴细胞对同种异体免疫反应的表达和产生 环孢素和FK506对肝细胞培养的影响 代谢物；检查移植物内细胞因子的潜在相关性 移植物内的转录本和全身浓度 免疫抑制剂；并检查潜在的相关性或缺乏 移植物内细胞因子谱与细胞因子的相关性 使用患者淋巴细胞和供者在体外生成的简档 同种异体抗原。

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.