We have extensive experiences in synthesising glucuronides using either scalable biotransformation or proprietary chemical methods.
Structures of glucuronides in the public domain which Hypha have produced for clients are illustrated in this case study.
Glucuronides are common Phase II metabolites of drugs which are often needed as standards for bioanalysis and for DDI testing. For acyl glucuronides, additional safety assessments may be needed due to their potential ability to directly acylate proteins and undergo intramolecular rearrangement producing reactive aldehydes leading to protein glycation. However, not all acyl glucuronides cause problems, and chemical reactivity assays, in vitro assessments, and evaluation of exposure in toxicology species is recommended in early clinical development to assess any risk.1
Glucuronides can be responsible for clinically relevant DDIs, such as those attributed to the acyl glucuronides of clopidogrel2 and gemfibrozil3, which selectively inhibit CYP2C8. Further issues can arise due to β-glucuronidase-mediated hydrolysis to the parent drug, the propensity for which differs due to marked species differences in expression of β-glucuronidases.4
We use both late-stage chemical synthesis and biotransformation methods to produce glucuronides for clients.
In addition, we have designed our methods to minimise instability resulting from the formation of acyl migration isomers. Synthesised glucuronides are purified with the option of structure confirmation by cryoprobe NMR spectroscopy and the provision of Certificates of Analysis.
References
1Walles et al., 2020. Chem Res Toxicol 33:1551-1560.
2Tornio et al., 2014. Clin Pharmacol Ther 96(4):498-507.
3Ogilvie et al., 2006. Drug Metab Dispos 34(1):191-197.
4Smith et al., 2018. Drug Metab Dispos 46(6):980-912.