Pang Minyeong, Jeon So Yeon, Choi Min-Koo, Jeon Ji-Hyeon, Ji Hye-Young, Choi Ji-Soo, Song Im-Sook
College of Pharmacy, Dankook University, Cheonan-si 31116, Korea.
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea.
Pharmaceutics. 2022 Jun 7;14(6):1210. doi: 10.3390/pharmaceutics14061210.
This study investigated the pharmacokinetics and tissue distribution of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor that is currently in phase three clinical trials. Enavogliflozin showed dose-proportional pharmacokinetics following intravenous and oral administration (doses of 0.3, 1, and 3 mg/kg) in both mice and rats. Oral bioavailability was 84.5-97.2% for mice and 56.3-62.1% for rats. Recovery of enavogliflozin as parent form from feces and urine was 39.3 ± 3.5% and 6.6 ± 0.7%, respectively, 72 h after its intravenous injection (1 mg/kg), suggesting higher biliary than urinary excretion in mice. Major biliary excretion was also suggested for rats, with 15.9 ± 5.9% in fecal recovery and 0.7 ± 0.2% in urinary recovery for 72 h, following intravenous injection (1 mg/kg). Enavogliflozin was highly distributed to the kidney, which was evidenced by the AUC ratio of kidney to plasma (i.e., 41.9 ± 7.7 in mice following its oral administration of 1 mg/kg) and showed slow elimination from the kidney (i.e., T of 29 h). It was also substantially distributed to the liver, stomach, and small and large intestine. In addition, the tissue distribution of enavogliflozin after single oral administration was not significantly altered by repeated oral administration for 7 days or 14 days. Overall, enavogliflozin displayed linear pharmacokinetics following intravenous and oral administration, significant kidney distribution, and favorable biliary excretion, but it was not accumulated in the plasma and major distributed tissues, following repeated oral administration for 2 weeks. These features may be beneficial for drug efficacy. However, species differences between rats and mice in metabolism and oral bioavailability should be considered as drug development continues.
本研究调查了恩格列净（一种新型钠-葡萄糖协同转运蛋白2抑制剂，目前正处于三期临床试验阶段）的药代动力学和组织分布情况。在小鼠和大鼠中，静脉注射和口服恩格列净（剂量分别为0.3、1和3mg/kg）后，其药代动力学呈剂量比例关系。小鼠的口服生物利用度为84.5 - 97.2%，大鼠为56.3 - 62.1%。静脉注射（1mg/kg）72小时后，恩格列净以原形从粪便和尿液中的回收率分别为39.3±3.5%和6.6±0.7%，表明小鼠中胆汁排泄高于尿液排泄。大鼠也显示出主要经胆汁排泄，静脉注射（1mg/kg）72小时后，粪便回收率为15.9±5.9%，尿液回收率为0.7±0.2%。恩格列净在肾脏中高度分布，口服1mg/kg后小鼠肾脏与血浆的AUC比值（即41.9±7.7）证明了这一点，且其从肾脏的消除缓慢（即半衰期为29小时）。它在肝脏、胃以及小肠和大肠中也有大量分布。此外，单次口服给药后恩格列净的组织分布在重复口服给药7天或14天后没有显著改变。总体而言，静脉注射和口服恩格列净后呈现线性药代动力学，有显著的肾脏分布和良好的胆汁排泄，但在重复口服给药2周后，它不会在血浆和主要分布组织中蓄积。这些特性可能对药物疗效有益。然而，随着药物研发的继续，应考虑大鼠和小鼠在代谢和口服生物利用度方面的种属差异。
