The metabolite profiling of YR-1702 injection in human plasma, urine and feces by HPLC-Q-TOF-MS/MS

YR-1702, a hybrid mu/kappa/delta receptor agonist, is modified from the traditional opioid analgesic dezocine. It had shown both excellent analgesic effect and lower addiction in phase I clinical trial in China, however, the metabolic pathway of YR-1702 in humans remains unelucidated.The goals of this study are to characterise the metabolism of YR-1702 in human liver microsomes (HLMs) and patients with chronic non-cancer pain by high performance liquid chromatography-coupled with quadrupole-time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS).The results showed that a total of twelve metabolites were identified in HLMs, in which 7, 6 and 5 metabolites were also found in human plasma, urine and feces, respectively. And the major metabolic pathways include mono-hydroxylation, di-hydroxylation, dehydrogenation and glucuronidation. The locations of hydroxylation and dehydrogenation were identified by the signature fragments of the metabolites.The relative contents of the metabolites in human plasma were also evaluated, in which the main metabolite M1 notably accounting for more than 14% of the total drug exposure. This study would contribute to the understanding of the in vivo metabolite profile of YR-1702 injection for future use.

Automated summary

YR-1702, a modified opioid analgesic, showed excellent analgesic effect and lower addiction in phase I clinical trial in China. However, its metabolic pathway in humans is still unclear. This study characterised the metabolism of YR-1702 in human liver microsomes and patients with chronic non-cancer pain using HPLC-Q-TOF-MS/MS. Results showed 12 metabolites, with 7, 6, and 5 metabolites found in human plasma, urine, and feces, respectively. The main metabolic pathways include hydroxylation, dehydrogenation, and glucuronidation. This study contributes to the understanding of YR-1702's in vivo metabolite profile for future use.