UDP-glucuronosyltransferase (UGT) (UGT)

UDP-glucuronosyltransferases (UGTs) are a superfamily of phase II metabolic enzymes that catalyze the transfer of glucuronic acid from UDP-glucuronic acid to various lipophilic substrates, including drugs and endogenous compounds (Kemp et al., 2002). In the case of raloxifene, a selective estrogen receptor modulator used for osteoporosis and breast cancer prevention, glucuronidation is the primary metabolic pathway, as the drug undergoes extensive first-pass metabolism (DrugBank, DB00481). The specific isoforms responsible for this process are UGT1A1, UGT1A8, UGT1A9, and UGT1A10, which are expressed in the liver and gastrointestinal tract (Jeong et al., 2021). These enzymes convert raloxifene into its 4'-glucuronide and 6-glucuronide metabolites, which are then excreted via the bile. Because raloxifene's bioavailability is low (approximately 2%) due to this rapid metabolism, the activity of these UGTs is a major determinant of its systemic exposure. Genetic variations in these enzymes, such as the UGT1A1*28 polymorphism, can lead to inter-individual differences in drug clearance and potential drug-drug interactions with other UGT substrates like irinotecan or bilirubin (UniProt, P22309).

Other names

UGTsUDP-glucuronyltransferaseGlucuronosyltransferaseUDPGTUGT1A1UGT1A8UGT1A9UGT1A10

Catalyzes the conjugation of glucuronic acid from UDP-glucuronic acid to lipophilic substrates, increasing their water solubility for biliary or renal excretion.