IMMUNOPHARMACOKINETICS AND IMMUNOPHARMACODYNAMICS

免疫药代动力学和免疫药效动力学

基本信息

批准号：
6349125
负责人：
LESLIE Z BENET
金额：
$ 2.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2001-07-31
项目状态：
已结题

项目摘要

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.

该单元的目的是定义和表征药代动力学免疫抑制剂的代谢，并发展和表征免疫抑制活性的度量可以与免疫调节剂的药代动力学特别强调环孢菌素，FK506和泼尼松/泼尼松龙。这些高度有效，如以及潜在的有毒，药物经常被浓度监测移植患者，但在改善方面几乎没有明显的成功治疗结果。我们假设该研究定量药物浓度之间的关系以及代谢物，具有反映器官作用部位的免疫学指标，例如在肝活检中，可能会导致对相关的药代动力学/药效学相关性的潜力。我们进一步假设对酶促过程的理解涉及，将导致对多种药物的理性解释与免疫抑制剂发现的相互作用。我们专门计划a）表征药代动力学和代谢免疫抑制剂的各个方面和b）表征对细胞因子的免疫抑制剂（IL-2，IL-4，IL-5，IL-10和IFN- 伽玛）基因表达和产生。在要进行的研究中计划表征负责代谢的P-450同工酶雄性和雌性大鼠亚细胞肝的环孢菌素和FK506和FK506 肠道级分，体内和体外，以及一系列的影响诱导者；确定环孢素和FK506的体内药代动力学在对照大鼠和大鼠中诱导的选定药物；在控制和肝脏中移植的大鼠，确定肝活检和相应的全身性环孢菌素和FK506及其代谢产物的浓度；在健康方面口服和静脉注射环孢素的志愿者表征诱导剂，例如乙基雌二醇，利福平和共轭雌激素；定量环孢菌素和 FK506及其在肝活检中的代谢物和全身性肝移植患者的循环以及特征这些活检的肝P-450和细胞因子基因表达和生产。研究还将：评估和分析细胞因子基因人类淋巴细胞的表达和生产响应同种异体在存在环孢素和FK506的情况下，肝细胞培养代谢物；检查内部细胞因子的潜在相关性具有内部和全身浓度的成绩单免疫抑制剂；并检查潜在的相关性或缺乏内部细胞因子谱与细胞因子之间的相关性使用患者的淋巴细胞和供体在体外产生的曲线同种。