Pharmacokinetics & Genomics in Glomerular Diseases

描述(由申请人提供)： 自身免疫相关肾脏疾病的治疗方法，如ANCA血管炎，在过去几年中相对没有改变，并与毒性和治疗失败相关。我们的长期目标是评估与药物代谢和转运相关的药代动力学和药物基因组学因素，以了解和改善ANCA血管炎的肾脏治疗反应。中心假设是，在ANCA血管炎患者中，环磷酰胺的代谢和糖皮质激素的运输是不同的，这些差异解释了肾脏结局的不同。结果差异是由于P-糖蛋白的药物转运和CYP 450代谢酶的药物代谢的基因和表型差异，导致糖皮质激素和环磷酰胺的剂量不足。 这项建议将通过ANCA血管炎患者的表型和基因分型(用于环磷酰胺的代谢和P-糖蛋白的运输)来研究活性和基因多态对肾脏治疗结果反应的作用。此外，还将利用微阵列技术分析用于表型评估的P-糖蛋白编码基因和CyP450酶在白细胞中的表达，以探索进一步评估这种非侵入性检测方法预测表型的可能性。将用探针药物进行功能表型分析，以评估P-糖蛋白(非索非那定)和相关的CYP 450酶[CYP 2C9(氟比洛芬)、2B6(安非他酮)和3A4(红霉素)]。与肾脏和其他临床结果测量一起，计划中的基因分型和表型评估测试应该提供对治疗结果差异的一些了解。还将评估基因型和表型之间的相关性。 所描述的研究项目是肾内科助理教授喜悦博士计划的5年K23职业发展。她的导师罗纳德·福尔克博士是肾病科主任，也是诊断和治疗肾小球疾病的专家。她的合作导师金·布劳威尔博士是药物运输和新陈代谢领域的专家。申请者与她的导师一起，利用医学院和药学院的资源，设计了一个教学、临床和实验室研究相结合的计划。这项计划的目标是提高申请者的技能，成为一名独立的肾病临床研究员，拥有药物运输和代谢方面的专业知识。选择在这笔赠款领域具有专业知识的合作者将促进喜悦博士的职业发展。

DESCRIPTION (provided by applicant): Treatment approaches for autoimmune related kidney diseases such as ANCA vasculitis have been relatively non-altered over the last several years and are associated with toxicity and treatment failures. Our long term-goal is to evaluate the pharmacokinetic and pharmacogenomic factors associated with drug metabolism and transport in order to understand and improve renal treatment responses in ANCA vasculitis. The central hypothesis is that the metabolism of cyclophosphamide and transport of glucocorticoids are different in individual patients with ANCA vasculitis and these differences account for variations in renal outcomes. The outcomes differences are due to genotypic and phenotypic variations in drug transport by P-glycoprotein and drug metabolism by CYP 450 metabolizing enzymes, that lead to inadequate dosing of glucocorticoids and cyclophosphamide. This proposal will phenotype and genotype ANCA vasculitis patients (for metabolism of cyclophosphamide and transport of P-glycoprotein) to investigate the role of activity and polymorphisms to renal outcome responses to treatment. Leukocyte expression of the genes encoding P-glycoprotein and CYP 450 enzymes for assessment of phenotype will also be analyzed by microarray technology to explore the potential for further evaluation of this noninvasive testing method for prediction of phenotype. Functional phenotyping with probe drugs will be performed to evaluate P-glycoprotein (fexofenadine), and relevant CYP 450 enzymes [CYP 2C9 (flurbiprofen), 2B6 (bupropion), and 3A4 (erythromycin)]. Together with renal and other clinical outcome measures, the planned genotyping and phenotyping assessments tests should provide some understanding of treatment outcome differences. The correlations between genotype and phenotype will also be evaluated. The research projects described are the planned 5-year K23 career development for Dr. Melanie S. Joy, Assistant Professor in the Division of Nephrology. Her mentor, Dr. Ronald Falk, is the Division Chief of Nephrology and an expert in the diagnosis and treatment of glomerular diseases. Her co-mentor, Dr. Kim Brouwer, is an expert in the area of drug transport and metabolism. Together with her mentors, the applicant has devised a combined didactic, clinical, and laboratory research plan, using resources from the Schools of Medicine and Pharmacy. The goal of this plan is to enhance the applicant's skills to become an independent nephrology clinical investigator with expertise in drug transport and metabolism. The selection of collaborators with expertise in the areas of this grant will enhance the career development of Dr. Joy.