In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes

Autor:	Dong Kyun Kim, Hye Suk Lee, Won-Gu Choi, Sangkyu Lee, Ju-Hyun Kim, Hye-Young Ji, Ji-Soo Choi, Im-Sook Song
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	chemistry.chemical_classification CYP3A4 Pharmaceutical Science lcsh:RS1-441 SGLT2 inhibitor Metabolism 030226 pharmacology & pharmacy Article UGT2B7 Hydroxylation lcsh:Pharmacy and materia medica 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Enzyme chemistry Biochemistry CYP DWP16001 030212 general & internal medicine SGLT2 Inhibitor Cotransporter metabolism UGT Drug metabolism
Zdroj:	Pharmaceutics Volume 12 Issue 9 Pharmaceutics, Vol 12, Iss 865, p 865 (2020)
ISSN:	1999-4923
DOI:	10.3390/pharmaceutics12090865
Popis:	DWP16001 is currently in a phase 2 clinical trial as a novel anti-diabetes drug for the treatment of type 2 diabetes by selective inhibition of sodium-glucose cotransporter 2. This in vitro study was performed to compare the metabolism of DWP16001 in human, dog, monkey, mouse, and rat hepatocytes, and the drug-metabolizing enzymes responsible for the metabolism of DWP16001 were characterized using recombinant human cytochrome 450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes expressed from cDNAs. The hepatic extraction ratio of DWP16001 in five species ranged from 0.15 to 0.56, suggesting that DWP16001 may be subject to species-dependent and weak-to-moderate hepatic metabolism. Five phase I metabolites (M1&ndash M5) produced by oxidation as well as three DWP16001 glucuronides (U1&ndash U3) and two hydroxy-DWP16001 (M1) glucuronides (U4, U5), were identified from hepatocytes incubated with DWP16001 by liquid chromatography-high resolution mass spectrometry. In human hepatocytes, M1, M2, M3, U1, and U2 were identified. Formation of M1 and M2 from DWP16001 was catalyzed by CYP3A4 and CYP2C19. M3 was produced by hydroxylation of M1, while M4 was produced by hydroxylation of M2 both hydroxylation reactions were catalyzed by CYP3A4. The formation of U1 was catalyzed by UGT2B7, but UGT1A4, UGT1A9, and UGT2B7 contributed to the formation of U2. In conclusion, DWP16001 is a substrate for CYP3A4, CYP2C19, UGT1A4, UGT1A9, and UGT2B7 enzymes. Overall, DWP16001 is weakly metabolized in human hepatocytes, but there is a potential for the pharmacokinetic modulation and drug&ndash drug interactions, involved in the responsible metabolizing enzymes of DWP16001 in humans.
Databáze:	OpenAIRE
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