In vitro glucuronidation of fenofibric acid by human UDP- glucuronosyltransferases and liver microsomes

Fenofibric acid (FA), the active moiety of fenofibrate, is an agonist of the peroxisome proliferator-activated nuclear receptor α that modulates triglyceride and cholesterol profiles. Lipid response to fenofibrate and FA serum concentrations is highly variable. Although FA is reported to be almost exclusively inactivated by UDP-glucuronosyltransferases (UGTs) into FA-glucuronide (FA-G), the contribution of UGT isoenzymes has never been systematically assessed. Heterologously expressed human UGT1A and UGT2B and their coding variants were tested for FA glucuronidation using liquid chromatography/mass spectrometry. Recombinant UGT2B7 presented the highest V_max/K_m value (2.10 μl/min/mg), 16-fold higher than the activity of other reactive UGTs, namely, UGT1A3, UGT1A6, and UGT1A9 (0.13, 0.09, and 0.02 μl/min/mg, respectively). UGT2B7.1 (His²⁶⁸) and UGT2B7.2 (Tyr²⁶⁸) enzyme activity was similar, whereas UGT1A3.2 (R¹¹A⁴⁷), UGT1A3.3 (Trp¹¹), and UGT1A9.3 (Thr³³) showed 61 to 96% reduced V_max/K_m values compared with the respective (1) reference proteins. FA-G formation by a human liver bank (n = 48) varied by 10-fold, but the rate of formation was not associated with common genetic variations in UGT1A3, UGT1A6, UGT1A9, and UGT2B7. Correlation with activities for the probe substrates zidovudine (UGT2B7; r ² = 0.75), mycophenolic acid (UGT1A9; r² = 0.42), fulvestrant (UGT1A3; r² = 0.36), but not serotonin (UGT1A6; r ² = 0.06) indicated a primary role for UGT2B7 and lesser roles of UGT1A9 and UGT1A3 in hepatic FA glucuronidation. This was confirmed by a strong correlation of FA-G formation with UGT2B7 protein content and inhibition by fluconazole, a known UGT2B7 selective inhibitor. Additional studies are required to identify genetic factors contributing to the observed FA glucuronidation variability.