Disposition of mycophenolic acid and its glucuronide metabolites in subjects with glomerulonephritis: Implications of genes and effects on kidney outcomes.

摘要

Glomerulonephritis is the third most frequent cause of end-stage kidney disease in the U.S. population. Treatments include immunosuppressant agents such as mycophenolate mofetil. The purpose of undertaking the studies included in this dissertation were to assess the pharmacokinetic alterations of mycophenolic acid in glomerulonephritis, to evaluate the role of patient-level demographic data, clinical data, and genomic alterations on pharmacokinetics, and to evaluate determinants of treatment-related outcomes. We evaluated the pharmacokinetics of mycophenolic acid in 45 patients receiving maintenance mycophenolic acid therapy. Pharmacogenomic assessments were conducted in 85 patients to evaluate genotype frequencies of drug metabolizing enzymes (uridine diphosphate glucuronosyltransferases; UGTs) and drug transporters (including multidrug resistance protein; MDR1) and mycophenolic acid disposition and relative risk of autoimmune diseases. mRNA expression patterns and their relationships to genomics were conducted in 45 patients. The pharmacokinetics showed enhanced oral clearance and reduced metabolic ratios in glomerulonephritis patients. Pharmacokinetics were more highly influenced by serum creatinine/creatinine clearance, urinary protein excretion, race, and gender, than single nucleotide polymorphisms in the UGTs or MDR1. The expression of transcript for drug metabolizing genes and transporter genes was variable across SLE and SVV treated versus untreated patients and healthy controls. The drug transporters were expressed in most patients, while the UGTs were expressed in only 50% of patients. Differences in transcript expression by race, treatment, disease, and genotypes were demonstrated. A disease-gene association risk was found in the study; the relative risk of SVV was increased in patients who were heterozygous or homozygous for the UGT2B7 C802T polymorphism. Kidney-related outcomes, as assessed by urinary protein to creatinine ratio, were worsened in patients with the UGT1A7 C622T polymorphism and improved with the MDR1 C3435T polymorphism. Composite outcomes (dialysis, death, or transplantation) were increased in patients who had reduced transcript expression for ABCB1 in peripheral blood leukocytes. The conducted studies demonstrated the highly complex relationships between drug disposition, patient-level clinical and demographic data, and genome-level variability. Numerous opportunities exist to further delineate these relationships in cell-based assays, animal models of glomerulonephritis, and larger translational studies that assess serial measurements of drug exposure and transcript expression.