In vitro inhibition of UGT1A3, UGT1A4 by ursolic acid and oleanolic acid and drug-drug interaction risk prediction

1. Ursolic acid (UA) and oleanolic acid (OA) may have important activity relevant to health and disease prevention. Thus, we studied the activity of UA and OA on UDP-glucuronosyltransferases (UGTs) and used trifluoperazine as a probe substrate to test UGT1A4 activity. Recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as a probe reaction for other UGT isoforms. 2. UA and OA inhibited UGT1A3 and UGT1A4 activity but did not inhibit other tested UGT isoforms. 3. UA-mediated inhibition of UGT1A3 catalyzed 4-MU-beta-glucuronidation was via competitive inhibition (IC50 0.391 +/- 0.013 mu M; K-i 0.185 +/- 0.015 mu M). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 2.651 +/- 0.201 mu M; K-i 1.334 +/- 0.146 mu M). 4. OA offered mixed inhibition of UGT1A3-mediated 4-MU-beta-glucuronidation (IC50 0.336 +/- 0.013 mu M; K-i 0.176 +/- 0.007 mu M) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 5.468 +/- 0.697 mu M; K-i 6.298 +/- 0.891 mu M). 5. Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.