Pharmacokinetics & Genomics in Glomerular Diseases

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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.