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

Abstract

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-β-d-glucuronidation was via competitive inhibition (IC₅₀ 0.391 ± 0.013 μM; K_i 0.185 ± 0.015 μM). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC₅₀ 2.651 ± 0.201 μM; K_i 1.334 ± 0.146 μM).

4. OA offered mixed inhibition of UGT1A3-mediated 4-MU-β-d-glucuronidation (IC₅₀ 0.336 ± 0.013 μM; K_i 0.176 ± 0.007 μM) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC₅₀ 5.468 ± 0.697 μM; K_i 6.298 ± 0.891 μM).

5. Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.

Keywords:

• Drug–drug interactions
• oleanolic acid
• risk prediction
• UDP-glucutonosyltransferases
• ursolic acid

Declaration of interest

The authors have declared that there are no conflicts of interest.

This work was supported by National Nature Science Fund [No. 81160411, 81560606], Jiangxi Provincial Nature Science Fund [No. 20151BAB205084], Jiangxi Province Young Scientist Supporting Project [No. 20133BCB23006], Science and Technology Research Project of Education Department of Jiangxi Province (No. 150036), and 2015 annual innovation special fund of Nanchang University [No. cx2015186].