Glucuronides as Potential Anionic Substrates of Human Cytochrome P450 2C8 (CYP2C8)

Glucuronidation is in general considered as a terminal metabolic step that leads to direct elimination of drugs and generally abolishes their biological activity. However, there is growing evidence to suggest that glucuronides can be ligands of human CYP2C8, making CYP2C8 distinct from the other CYP isoforms. Several classes of glucuronide conjugates, which include acyl glucuronides, ether glucuronides, N-glucuronides, and carbamoyl glucuronides, have been shown to be substrates or time-dependent inhibitors of CYP2C8. Although the structures of CYP2C8-glucuronide complexes have not been determined, the structural features of CYP2C8 active site support its binding to anionic and bulky ligands like glucuronides. As interaction perpetrators with CYP2C8, glucuronides of gemfibrozil and clopidogrel showed marked clinical drug-drug interactions (e.g., with cerivastatin and repaglinide), which are more than expected from the parent drug. This review summarizes glucuronides as CYP2C8 ligands and the active-site structural features of CYP2C8 that allow potential binding to glucuronides.