N-glucuronidation of drugs and other xenobiotics by human and animal UDP-glucuronosyltransferases

Abstract

1. Metabolic disposition of drugs and other xenobiotics includes glucuronidation reactions that are catalyzed by the uridine diphosphate glucuronosyltransferases (UGTs). The most common glucuronidation reactions are O- and N-glucuronidation and in this review, we discuss both, while the emphasis is on N-glucuronidation.

2. Interspecies difference in glucuronidation is another central issue in this review due to its importance in drug development. Accordingly, the available data on glucuronidation in different animals comes mainly from the species that are used in preclinical studies to assess the safety of drugs under development.

3. Both O- and N-glucuronidation reactions are chemically diverse. Different O-glucuronidation reactions are described and discussed, and many drugs that undergo such reactions are indicated. The compounds that undergo N-glucuronidation include primary aromatic amines, hydroxylamines, amides, tertiary aliphatic amines, and aromatic N-heterocycles.

4. The interspecies variability in N-glucuronidation is particularly high, above all when it comes to aliphatic tertiary amines and aromatic N-heterocycles.

5. The N-glucuronidation rates in humans are typically much higher than in animals, largely due to the activity of two enzymes, the extensively studied UGT1A4, and the more recently identified as a main player in N-glucuronidation, UGT2B10. We discuss both enzymes and review the findings that revealed the role of UGT2B10 in N-glucuronidation.

Keywords::

• N-glucuronidation
• UDP-glucuronosyltransferases
• species differences
• amines
• amides
• aromatic N-heterocycles
• UGT1A4
• UGT2B10

Acknowledgements

Ms Päivi Hirvensalo is acknowledged for her help in drawing figures.

Declaration of interest

Moshe Finel is grateful for the financial support of the Sigrid Juselius Foundation.