Abstract
Glucuronidation is the most common phase II reaction observed in the metabolism of drugs in humans, involving conjugation of small molecules to glucuronic acid by UDP-glucuronosyltransferases (UGTs). N-glucuronides can be formed as a result of aliphatic and aromatic conjugations with pyrazole, pyridine, pyridazine, pyrrolidine, pyrimidine, imidazole, triazole, and tetrazole moieties all being susceptible ring structures.
Interspecies variability in N-glucuronidation is relatively high and is compounded by much higher rates of N-glucuronidation in humans. This is largely due to UGT1A4 and UGT2B10. This species difference can lead to the observation of disproportionate N-glucuronides during studies in humans.
This poster illustrates the use of late-stage chemical glucuronidation and microbial biotransformation to provide scalable quantities of UGT-1A4 mediated pyrazole-linked N-glucuronides of two clinical stage drugs for definitive structure elucidation by NMR and further testing of the metabolites.
Poster presented at: 50th Open DMDG Meeting, York, UK and APA meeting Boston, USA, 2024.