Major human circulating diglucuronide of GDC-0810
Our paper pick for July 2023 is an interesting and rare example of a discrete diglucuronide formed by glucuronidation on two different functional groups to a major circulating metabolite in humans.
M2 is predominantly formed from sequential acyl glucuronidation in the intestines followed by N-glucuronidation in the liver.
There are a few interesting facets to this biotransformation; firstly that N-glucuronidation being more common in humans due to the activity of UGT1A4 and UGT2B10, results in the absence of M4 in animal species. Secondly that acyl glucuronidation to M6 was generally compartmentalised in the intestine rather than the liver due to the involvement of UGTs 1A8/1A7 and 1A1. These elements help explain the unpredicted appearance of the discrete diglucuronide M2 as a major circulating metabolite in humans.