Abstract 20: Evidence of UGT2B7 as a Pharmacogenetic Determinant of Variability in Serum Fenofibric Acid Levels in Human Subjects
BACKGROUND: Genetic polymorphisms affecting the drug metabolizing gene [UDP-glucuronosyltransferases or UGTs-(specifically UGT2B7)] have been reported by our group as a significant source of variability in the lipid-lowering response to fenofibrate. Fenofibrate’s lipid-lowering response displays exceptionally high inter-subject variability which may represent one source of the mixed results from outcome based clinical trials such as ACCORD and FIELD. Given the association between lipid response and fenofibric acid serum concentrations, the purpose of this study was to investigate the pharmacokinetic significance of the UGT2B7 promoter SNP (A-327G SNP (rs7662029)) on serum fenofibric acid concentrations in humans.
METHODS: Using a genotype guided approach, we prospectively recruited subjects (>18 years) whose genotype was either AA or GG for UGT2B7 A-327G to receive 28 days once daily fenofibrate (145mg). Steady-state area under the serum fenofibrate concentration vs. time curve (AUC0-24) was calculated from 8 determinations on day 28. Fasting lipid profiles where collected at baseline and after fenofibrate administration.
RESULTS: 49 (39% male) individuals with a mean (±SD) age of 33 (±11.8) years completed the study. This included 26 with AA and 23 with GG for UGT2B7 A-327G. The mean (±SD) AUC0-24 was 218.4±98 μg*hr/mL for AA and 300±131 μg*hr/mL for the GG individuals (p=0.017). Overall, associations between higher AUC0-24 and percent change in lipid fraction from baseline, were confirmed for TG (r2=0.26, p-value= 0.0002), total cholesterol (r2=0.12, p=0.014), LDL-C (r2=0.17, p= 0.0032,), non-HDL-C (r2=0.11, p=0.019) but not HDL-C (NS). Adjusted for BMI, UGT2B7 A-327G explained 22% of the fenofibric acid AUC0-24, with AA individuals having 27.3% lower AUC0-24 compared to GG individuals.
CONCLUSIONS: We confirm UGT2B7 A-327G to be a significant determinant of serum fenofibric acid concentrations and hence a potential important source of fenofibrate’s variability in lipid response and/or clinical outcomes.
- © 2012 by American Heart Association, Inc.