Deep understanding of the interaction between thienorphine and UDP-glucuronosyltransferase (UGT) isoforms

Abstract

1. Thienorphine has been demonstrated to be a potent, long-acting partial opioid agonist. It is being developed as a good candidate to treat opioid dependence.

2. The thienorphine’s glucuronide was detected after thienorphine was incubated with human liver microsomes (HLMs). Recombinant UGT isoforms screening experiment and enzyme kinetic study showed that UGT1A1 completely contributed to the glucuronidation of thienorphine.

3. Among the tested UGT isoforms, UGT1A3 and UGT2B7 were inhibited by thienorphine, with other UGT isoforms negligibly influenced. The inhibition type is competitive, and inhibition kinetic parameters (K_i) were 1.65 and 5.27 μM for UGT1A3 and UGT2B7, respectively. However, due to low plasma concentration of thienorphine, in vivo drug–drug interaction might not occur.

Keywords::

• Thienorphine
• UDP-glucuronosyltransferase (UGT)
• drug–drug interaction