Effects of mitragynine and 7‑hydroxymitragynine (the alkaloids of Mitragyna speciosa Korth) on 4‑methylumbelliferone glucuronidation in rat and human liver microsomes and recombinant human uridine 5’‑diphospho‑glucuronosyltransferase isoforms

Background: Glucuronidation catalyzed by uridine 5’‑diphospho‑glucuronosyltransferase (UGT) is a major phase II drug metabolism reaction which facilitates drug elimination. Inhibition of UGT activity can cause drug‑drug interaction. Therefore, it is important to determine the inhibitory potentials of drugs on glucuronidation. Objectives: The objective was to evaluate the inhibitory potentials of mitragynine, 7‑hydroxymitragynine, ketamine and buprenorphine, respectively on 4‑methylumbelliferone (4‑MU) glucuronidation in rat liver microsomes, human liver microsomes and recombinant human UGT1A1 and UGT2B7 isoforms. Materials and Methods: The effects of the above four compounds on the formation of 4‑MU glucuronide from 4‑MU by rat liver microsomes, human liver microsomes, recombinant human UGT1A1 and UGT2B7 isoforms were determined using high‑performance liquid chromatography with ultraviolet detection. Results: For rat liver microsomes, ketamine strongly inhibited 4‑MU glucuronidation with an IC50 value of 6.21 ± 1.51 μM followed by buprenorphine with an IC₅₀ value of 73.22 ± 1.63 μM. For human liver microsomes, buprenorphine strongly inhibited 4‑MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM. For human UGT1A1 isoform, 7‑hydroxymitragynine strongly inhibited 4‑MU glucuronidation with an IC₅₀ value of 7.13 ± 1.16 μM. For human UGT2B7 isoform, buprenorphine strongly inhibited 4‑MU glucuronidation followed by 7‑hydroxymitragynine and ketamine with respective IC₅₀ values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM. Conclusion: These data indicate the possibility of drug‑drug interaction if 7‑hydroxymitragynine, ketamine, and buprenorphine are co‑administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity. In addition, if 7‑hydroxymitragynine is to be taken with other drugs that are