Regio- and Stereospecific N-Glucuronidation of Medetomidine: The Differences between UDP Glucuronosyltransferase (UGT) 1A4 and UGT2B10 Account for the Complex Kinetics of Human Liver Microsomes

Abstract

ABSTRACT:Medetomidine is a chiral imidazole derivate whose dextroenantiomer is pharmacologically active.

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

“…Although initially considered an orphan enzyme, more recent studies have shown that UGT2B10, like UGT1A4, catalyzes the N-glucuronidation of a number of xenobiotics that incorporate an aliphatic tertiary amine or aromatic N-heterocyclic group (Kaivosaari et al, 2011). Known substrates are nicotine and its oxidation product cotinine (Chen et al, 2007;Kaivosaari et al, 2007); desloratadine (Kazmi et al, 2015a); medetomidine (Kaivosaari et al, 2008); the tricyclic antidepressants (TCAs) amitriptyline, clomipramine, imipramine, and trimipramine (Chen et al, 2007;Zhou et al, 2010;Kato et al, 2013); several tobacco-specific nitrosamines (Chen et al, 2008); RO5263397 (Fowler et al, 2015); and miscellaneous drugs that include diphenhydramine, ketoconazole, ketotifen, midazolam, olanzapine, pizotifen, and tamoxifen (Erickson-Ridout et al, 2011;Kato et al, 2013). Consistent with the known selectivity of UGT1A4 for N-glucuronidation (Kubota et al, 2007), most, if not all, UGT2B10 substrates are additionally glucuronidated by UGT1A4 and biphasic kinetics are frequently observed when human liver microsomes (HLM) are used as the enzyme source (Kaivosaari et al, 2011;Kato et al, 2013).…”

Bucolome N-Glucuronide Formation: Species Differences and Identification of Human UDP-Glucuronosyltransferase Isoforms

“…In recent years, it has been reported that hepatic UGT1A4 and 2B10 catalyze the N-glucuronidation of aromatic N-heterocycles in humans [18,19]. However, BCP-NG formation by hUGT1A4 was <10 pmol equivalents/min/mg protein (Figure 3).…”

“…However, BCP-NG formation by hUGT1A4 was <10 pmol equivalents/min/mg protein (Figure 3). The level of hUGT1A4 mRNA in tissues other than the liver is either very low [18,19] or below the detection limit [25]. Therefore, it seems that the contribution of UGT1A4 to BCP-NG formation is negligible.…”

“…Therefore, it seems that the contribution of UGT1A4 to BCP-NG formation is negligible. hUGT2B10 has only been detected in the liver and small intestine [18,19], and the level of hUGT2B10 mRNA in the small intestine is only 0.05% of that in the liver. The ortholog of human 2B10 has not been detected in animals [20], while the UGT1A1 family has been detected in various species [20,[26][27] and a number of different tissues [28][29][30].…”

“…A number of aromatic N-heterocycles with five-and six-member rings, such as imidazoles, pyrazoles, triazines, tetrazoles, and pyridines are subject to N-glucuronidation. However, N-glucuronidation of the pyrimidine skelton of barbiturates has not been mentioned in recent review articles [18][19][20].…”