ABSTRACT
The metabolism study of radiolabeled drugs plays an important role in the development of new drugs. It provides information on drug absorption, metabolism, tissue distribution and excretion, and plays an irreplaceable role in the metabolite safety evaluation and mass balance of new drugs. The new guidance draft on clinical trials of radiolabeled drugs recently released by the US FDA puts forward higher standards and has been widely concerned by the industry. In recent years, in the research and development of new drugs in China, 14C labeled drugs have been used to carry out clinical metabolism studies, which has overcome key technical bottlenecks and accumulated experience. This paper summarizes the above research progress, analyzes the existing problems, and preliminarily looks forward to the future technological development and application.
ABSTRACT
Rocuronium bromide is an acetylcholine N2 receptor antagonist, which can be used as an auxiliary drug for general anesthesia. It has been reported that rocuronium has two possible metabolic pathways: N-dealkylation and O-deacetylation, which are mainly taken up by liver and excreted by bile in the form of primary drugs. In this paper, the metabolites of rocuronium in human bile were detected by UHPLC-QE-orbitrap-MS, thirteen metabolites were detected, including eleven phase I metabolites and two phase II metabolites, eleven of which had not been previously reported. At the same time, HEK293 cells overexpressing transporter were used to explore the transmembrane transport mechanism of rocuronium, the results showed that rocuronium was the substrate of MATE1, OCT1, OATP1B1 and OATP1B3. The above research results enrich the metabolic pathway of rocuronium in vivo, and put forward the possible transport mechanism of liver uptake and bile excretion, which can better guide the accurate and safe clinical drug application. The collection of human bile samples in this study was approved by the ethics committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Approval Number: 2019-775-130-01).