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

Abstract

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.

Complete Substrate Inhibition of Cytochrome P450 2C8 by AZD9496, an Oral Selective Estrogen Receptor Degrader

“…Indeed, non-M-M kinetics have been rationalized on the basis of simultaneous binding of multiple ligands within active sites (Atkins, 2005). P450s with large-enough active sites relative to their substrates would likely figure in such interactions and include CYP3A4 and CYP2C8 (Ma et al, 2017).…”

Metabolism and Disposition of Verinurad, a Uric Acid Reabsorption Inhibitor, in Humans

“…Interestingly, among all the CYP isoforms evaluated, only CYP2C8 was able to oxidize M1 to M8. Several glucuronide substrates have been identified as CYP2C8 ligands (Ma et al, 2017). Homology modeling has been used to examine substrate specificity of the CYP2C family (namely 2C8, 2C9, 2C18, and 2C19).…”

“…Several key amino acids have been identified in the CYP2C8 active site that afford substrate selectivity, namely Ser114, Phe205, and Ile476, which enable binding of hydrophilic substrates like glucuronides to the active site (Ridderstrom et al, 2001;Schoch et al, 2004;Johnson and Stout, 2005). Several drugs, including gemfibrozil and clopidogrel, form acylglucuronides that are strong CYP2C8 time-dependent inhibitors (Ma et al, 2017). The CYP2C8 time-dependent inhibition of M1 and M8 was not investigated but will be in future studies.…”

Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate

“…Drug interactions associated with clopidogrel could be frequently encountered in patient care (Kim et al, 2016;Xie et al, 2011). Recent studies documented that phase II metabolitesglucuronidescould be the ligands of human CYP2C8 (Ma, Fu, Khojasteh, Dalvie, & Zhang, 2017), and that CAG is known to be a potent, time-dependent inhibitor of CYP2C8 (Backman, Filppula, Niemi, & Neuvonen, 2016;Bergmann et al, 2016;Itkonen et al, 2016;Kim et al, 2016;Tornio et al, 2014). High plasma CAG concentrations would strongly inhibit the metabolism of the substrate drugs of CYP2C8, such as cerivastatin (Floyd et al, 2012), dasabuvir (Arya, Zhao, Reynolds, Mishra, & Younis, 2017;Shebley, Fu, Badri, Bow, & Fischer, 2017), desloratadine (Kazmi, Barbara, Yerino, & Parkinson, 2015), paclitaxel (Agergaard et al, 2017;Backman et al, 2016;Bergmann et al, 2016), pioglitazone (Itkonen et al, 2016;Kim et al, 2016), repaglinide (Tornio et al, 2014;Kim et al, 2016), and more, which would result in serious adverse drug reactions, such as cerivastatin-induced rhabdomyolysis (Floyd et al, 2012), pioglitazone-associated fluid retention (Itkonen et al, 2016), paclitaxel-related neurotoxicity (Bergmann et al, 2016), and repaglinide-mediated hypoglycemia (Tornio et al, 2014).…”