In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes
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, a...
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doaj-1a2e54366a22458880f4054e765ee2472020-11-25T03:42:23ZengMDPI AGPharmaceutics1999-49232020-09-011286586510.3390/pharmaceutics12090865In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal HepatocytesJu-Hyun Kim0Dong Kyun Kim1Won-Gu Choi2Hye-Young Ji3Ji-Soo Choi4Im-Sook Song5Sangkyu Lee6Hye Suk Lee7College of Pharmacy, Yeungnam University, Gyeongsan 38541, KoreaBK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, KoreaBK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, KoreaLife Science Institute, Daewoong Pharmaceutical Co. Ltd., Yongin 17028, KoreaLife Science Institute, Daewoong Pharmaceutical Co. Ltd., Yongin 17028, KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, KoreaBK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, KoreaDWP16001 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–M5) produced by oxidation as well as three DWP16001 glucuronides (U1–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–drug interactions, involved in the responsible metabolizing enzymes of DWP16001 in humans.https://www.mdpi.com/1999-4923/12/9/865DWP16001SGLT2 inhibitormetabolismCYPUGT |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ju-Hyun Kim Dong Kyun Kim Won-Gu Choi Hye-Young Ji Ji-Soo Choi Im-Sook Song Sangkyu Lee Hye Suk Lee |
spellingShingle |
Ju-Hyun Kim Dong Kyun Kim Won-Gu Choi Hye-Young Ji Ji-Soo Choi Im-Sook Song Sangkyu Lee Hye Suk Lee In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes Pharmaceutics DWP16001 SGLT2 inhibitor metabolism CYP UGT |
author_facet |
Ju-Hyun Kim Dong Kyun Kim Won-Gu Choi Hye-Young Ji Ji-Soo Choi Im-Sook Song Sangkyu Lee Hye Suk Lee |
author_sort |
Ju-Hyun Kim |
title |
In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes |
title_short |
In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes |
title_full |
In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes |
title_fullStr |
In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes |
title_full_unstemmed |
In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes |
title_sort |
in vitro metabolism of dwp16001, a novel sodium-glucose cotransporter 2 inhibitor, in human and animal hepatocytes |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-09-01 |
description |
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–M5) produced by oxidation as well as three DWP16001 glucuronides (U1–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–drug interactions, involved in the responsible metabolizing enzymes of DWP16001 in humans. |
topic |
DWP16001 SGLT2 inhibitor metabolism CYP UGT |
url |
https://www.mdpi.com/1999-4923/12/9/865 |
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