Pharmacokinetics & Genomics in Glomerular Diseases

描述（由申请人提供）： 在过去几年中，自身免疫相关肾脏疾病（如ANCA血管炎）的治疗方法相对没有改变，并且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。中心假设是环磷酰胺的代谢和糖皮质激素的转运在患有ANCA血管炎的个体患者中是不同的，并且这些差异解释了肾脏结局的变化。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型和表型差异，导致糖皮质激素和环磷酰胺的剂量不足。 本提案将对ANCA血管炎患者进行表型和基因分型（针对环磷酰胺代谢和P-糖蛋白转运），以研究活性和多态性对肾脏治疗结果反应的作用。还将通过微阵列技术分析用于评估表型的编码P-糖蛋白和P450酶的基因的白细胞表达，以探索进一步评价这种用于预测表型的非侵入性检测方法的潜力。将使用探针药物进行功能表型分析，以评价P-糖蛋白（非索非那定）和相关β 450酶[β 2C 9（氟比洛芬）、2B 6（安非他酮）和3A 4（红霉素）]。与肾脏和其他临床结局指标一起，计划的基因分型和表型评估试验应提供对治疗结局差异的一些了解。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为Melanie S博士计划的5年K23职业发展。乔伊，肾脏科助理教授。她的导师，罗纳德福尔克博士，是肾脏科主任和肾小球疾病的诊断和治疗专家。她的共同导师Kim Brouwer博士是药物转运和代谢领域的专家。与她的导师一起，申请人设计了一个结合教学，临床和实验室研究计划，利用医学和药学院的资源。该计划的目标是提高申请人的技能，成为一名独立的肾脏病学临床研究者，在药物转运和代谢方面具有专业知识。选择在该补助金领域具有专业知识的合作者将促进Joy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.