Pharmacokinetics & Genomics in Glomerular Diseases

药代动力学

• 批准号: 7111085
• 负责人: MELANIE S JOY
• 金额: $ 11.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111085
• 关键词: P glycoprotein; autoimmune disorder; bupropion; clinical research; cyclophosphamide; cytochrome P450; drug metabolism; erythromycin; genotype; glomerulonephritis; glucocorticoids; human subject; microarray technology; patient oriented research; pharmacogenetics; pharmacokinetics

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.

描述（由申请人提供）： 自身免疫相关肾脏疾病（例如 ANCA 血管炎）的治疗方法在过去几年中相对没有改变，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 ANCA 血管炎个体患者中是不同的，这些差异解释了肾脏结果的变化。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变化造成的，导致糖皮质激素和环磷酰胺的剂量不足。 该提案将对 ANCA 血管炎患者进行表型和基因型分析（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。用于评估表型的 P-糖蛋白和 CYP 450 酶编码基因的白细胞表达也将通过微阵列技术进行分析，以探索进一步评估这种用于预测表型的非侵入性测试方法的潜力。将使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 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，计划的基因分型和表型评估测试应该可以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病科助理教授 Melanie S. Joy 博士计划的 5 年 K23 职业发展。她的导师Ronald Falk博士是肾脏病科主任，也是肾小球疾病诊断和治疗方面的专家。她的合作导师 Kim Brouwer 博士是药物转运和代谢领域的专家。申请人与她的导师一起，利用医学院和药学院的资源，制定了一个综合教学、临床和实验室研究计划。该计划的目标是提高申请人的技能，成为一名具有药物转运和代谢专业知识的独立肾脏病临床研究者。选择在该资助领域具有专业知识的合作者将促进乔伊博士的职业发展。