Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans.

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Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A

Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans.

Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27.

PubMed ID

31432741 [ View in PubMed

]

Abstract

Bexagliflozin is a C-aryl glucoside inhibitor of human sodium-glucose linked transporter 2 (SGLT2) that undergoes oxidation and glucuronidation to form six principal metabolites in humans.In vitro metabolism by human liver microsomes and recombinant enzymes is primarily mediated by CYP3A4 and UGT1A9. Three major oxidation products and three major glucuronides have been identified in vivo. Metabolism by rats is mostly by oxidation whereas metabolism by monkeys and humans is mostly by glucuronidation. Metabolism by monkeys closely resembles metabolism by humans and all metabolites found in humans are also found in monkeys. A greater diversity of metabolites has been identified among human in vivo specimens than among in vitro reaction products.Following oral dosing of humans with (14)C-bexagliflozin, the 3'-O-glucuronide contributed 32% of the parent AUC and all other metabolites contributed <10%. Of the 91.6% of input radioactivity recovered, 51.1% was in faeces, predominantly as bexagliflozin, and 40.5% was in urine, largely as the 3'-O-glucuronide. Unidentified metabolites contributed 0.27% of the input radiolabel.A quantitative accounting for the metabolism and disposition of bexagliflozin in vivo has been developed.

DrugBank Data that Cites this Article

Drugs

Bexagliflozin

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Bexagliflozin	Cytochrome P450 2C8	Protein	Humans	Unknown	Substrate	Details
Bexagliflozin	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details
Bexagliflozin	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details
Bexagliflozin	UDP-glucuronosyltransferase 1-1	Protein	Humans	Unknown	Substrate	Details
Bexagliflozin	UDP-glucuronosyltransferase 1-9	Protein	Humans	Unknown	Substrate	Details

Drug Reactions

Reaction
Bexagliflozin DB12236 UDP-glucuronosyltransferase 1-9 UDP-glucuronosyltransferase 1-1 EGT0002149 DBMET03593	Details
Bexagliflozin DB12236 Cytochrome P450 3A4 EGT0001494 DBMET03594	Details
Bexagliflozin DB12236 Cytochrome P450 3A4 Cytochrome P450 2C8 Cytochrome P450 2D6 EGT0001301 DBMET03595	Details
Bexagliflozin DB12236 Cytochrome P450 3A4 Cytochrome P450 2D6 EGT0001663 DBMET03596	Details