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

Ju-Hyun Kim,Sangkyu Lee,Hye-Young Ji,Dong Kyun Kim,Im-Sook Song,Hye Suk Lee,Ji-Soo Choi,Won-Gu Choi

doi:10.3390/pharmaceutics12090865

Abstract

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.

Highlights

In 2019, approximately 463 million adults (20–79 years of age) were living with diabetes [1]
The hepatic extraction ratios of DWP16001 in human, dog, monkey, mouse, and rat were 0.22, 0.56, 0.43, 0.41, and 0.15, respectively; these findings suggested that DWP16001 is weakly metabolized in the rat and human liver but is moderately metabolized in the dog, monkey, and mouse liver
The metabolic stability of DWP16001 in human, dog, monkey, mouse, and rat hepatocytes resulted in hepatic extraction ratios of 0.22, 0.56, 0.43, 0.41, and 0.15, respectively; these findings indicated that DWP16001 is weakly metabolized in humans and rats, but moderately metabolized in dogs, monkeys, and mice (Table 1)

Summary

Introduction

In 2019, approximately 463 million adults (20–79 years of age) were living with diabetes [1]. Since the approval of dapagliflozin by the European Medicines Agency as the first SGLT2 inhibitor in 2012, multiple other SGLT2 inhibitors have been developed, including canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, and ertugliflozin [3,4,5] These SGLT2 inhibitors are effective in glycemic control in type 2 diabetic patients and effective in reducing cardiovascular events and improving renal outcomes [6,7,8,9,10]. The beneficial effect of empagliflozin, canagliflozin, and dapagliflozin treatment on the reduced hospitalization for heart failure and cardiovascular risk has been demonstrated in diabetic patients with heart failure from the multi-national clinical trials (i.e., the EMPA-REG OUTCOME trial, the CANVAS program, and the DECLARE-TIMI 58 trial) [6,7,8]. In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular event was lowered by the canagliflozin treatment [9,13] and by the empagliflozin treatment [10]

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Conclusion