Pharmacokinetics and Tissue Distribution of Enavogliflozin in Mice and Rats

Abstract

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., T1/2 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.

Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans

“…This predicted bioavailability ranged from 78.9% to 79.0% after a single dose of 0.2, 0.5, 1, 2 and 5 mg and at the steady-state after repeated doses of once-daily administration of 0.3, 0.5 and 1 mg enavogliflozin. Although there have been no clinical trials testing intravenous doses, the predicted oral bioavailability in humans is comparable to the reported values in the animal experiments, which were 84.5–97.2% in mice and 56.3–77.4% in rats [ 1 , 44 ]. Even though the absorption model had a simple structure (i.e., the first-order kinetics), the predicted exposure (AUC) and C max matched to the observed values well.…”

Study and exploration of the pharmacokinetics of traditional Tibetan medicine Ruyi Zhenbao tablets after single and long-term administration

“…A 50.0 µl volume of rat plasma was placed in a 2.0 ml centrifuge tube and 150 µl of methanol solution (80.0 ng ml −1 ) containing internal standard was added ( Polson et al, 2003 ; Pang et al, 2022 ). The solution was swirled for 1 min and then centrifuged for 15 min (12,700 rpm, 4°C).…”

A 52‐week efficacy and safety study of enavogliflozin versus dapagliflozin as an add‐on to metformin in patients with type 2 diabetes mellitus: ENHANCE‐M extension study

“…[6][7][8][9][10] Enavogliflozin is a novel SGLT-2-selective inhibitor developed in South Korea. 11 Its pharmacokinetic and pharmacodynamic properties were verified in preclinical studies involving in vitro and animal models and healthy volunteers, [12][13][14][15][16] and its efficacy and safety in patients with T2DM were confirmed in several randomized trials analysing various clinical scenarios. [17][18][19][20] In one of those trials, a double-blind (DB) randomized phase 3 study, the efficacy and safety of enavogliflozin (0.3 mg/day) as an add-on to metformin were verified against dapagliflozin (10 mg/day).…”