Kim Ju-Hyun, Kim Dong Kyun, Choi Won-Gu, Ji Hye-Young, Choi Ji-Soo, Song Im-Sook, Lee Sangkyu, Lee Hye Suk
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
BK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea.
Pharmaceutics. 2020 Sep 11;12(9):865. doi: 10.3390/pharmaceutics12090865.
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.
DWP16001作为一种新型抗糖尿病药物，目前正处于2期临床试验阶段，通过选择性抑制钠-葡萄糖协同转运蛋白2来治疗2型糖尿病。进行这项体外研究是为了比较DWP16001在人、犬、猴、小鼠和大鼠肝细胞中的代谢情况，并使用从cDNA表达的重组人细胞色素450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）来表征负责DWP16001代谢的药物代谢酶。DWP16001在这五个物种中的肝脏提取率在0.15至0.56之间，这表明DWP16001可能会受到物种依赖性以及弱至中度肝脏代谢的影响。通过液相色谱-高分辨率质谱法，从与DWP16001一起孵育的肝细胞中鉴定出了5种由氧化产生的I期代谢物（M1-M5）、3种DWP16001葡萄糖醛酸苷（U1-U3）以及2种羟基-DWP16001（M1）葡萄糖醛酸苷（U4、U5）。在人肝细胞中，鉴定出了M1、M2、M3、U1和U2。DWP16001形成M1和M2是由CYP3A4和CYP2C19催化的。M3是由M1羟基化产生的，而M4是由M2羟基化产生的；这两种羟基化反应均由CYP3A4催化。U1的形成是由UGT2B7催化的，但UGT1A4、UGT1A9和UGT2B7参与了U2的形成。总之，DWP16001是CYP3A4、CYP2C19、UGT1A4、UGT1A9和UGT2B7酶的底物。总体而言，DWP16001在人肝细胞中代谢较弱，但在人体内负责代谢的酶方面存在药代动力学调节和药物-药物相互作用的可能性。
