## 3 Results
### Envogliflozin Tissue Distribution  
To investigate the dose-dependent tissue distribution of enavogliflozin, concentrations in plasma and tissues--including the stomach, large intestine, small intestine, kidneys, liver, lungs, heart, testes, spleen, and brain--were analyzed after single oral administration of enavogliflozin at doses of 1 and 3 mg/kg in mice. Concentration-time profiles of each tissue and plasma are shown in Figure 5. Enavogliflozin was not detected in the brain; therefore, the brain was not included in this figure. The plasma concentration profiles were divided into three subsets according to the enavogliflozin concentrations in each tissue compared with its plasma concentration. Concentration profiles of enavogliflozin in the stomach, small intestine, large intestine, and liver showed similar patterns to that of plasma but with higher concentrations (Figure 5A,B at 1 mg/kg; Figure 5D,E at 3 mg/kg).  
\begin{table}
\begin{tabular}{c c c c c} \hline  & \multicolumn{4}{c}{**Dose**} \\ \cline{2-5}
**Parameter** & **Single** & **Repeated** & **Repeated** & **\(p\) Value** \\  & & **for 7 Days** & **for 14 Days** & \\ \hline T\({}_{\text{max}}\) (h) & 2.400 \(\pm\) 0.894 & 2.000 \(\pm\) 0.000 & 1.600 \(\pm\) 0.548 & 0.105 \\ C\({}_{\text{max}}\) (ng/mL) & 253.4 \(\pm\) 28.69 & 258.5 \(\pm\) 28.22 & 257.0 \(\pm\) 74.37 & 0.914 \\ T\({}_{1/2}\) (h) & 3.949 \(\pm\) 0.674 & 4.070 \(\pm\) 0.419 & 4.272 \(\pm\) 0.554 & 0.357 \\ AUC\({}_{\text{last}}\) (h-ng/mL) & 2047 \(\pm\) 389.1 & 1934 \(\pm\) 253.7 & 2066 \(\pm\) 516.8 & 0.533 \\ AUC\({}_{\text{co}}\) (h-ng/mL) & 2074 \(\pm\) 380.4 & 1966 \(\pm\) 263.9 & 2106 \(\pm\) 506.3 & 0.613 \\ MRT (h) & 5.867 \(\pm\) 0.242 & 5.763 \(\pm\) 0.583 & 6.220 \(\pm\) 0.368 & 0.174 \\ \hline \end{tabular} Data are expressed as the mean \(\pm\) SD (\(n=5\)). \(p\) value was calculated among three groups by the Kruskal–Wallis test.  
\end{table}
Table 6: Pharmacokine parameters of enavogliflozin in mice following single or repeated oral administration of enavogliflozin (1 mg/kg).  
Figure 4: Plasma concentration vs. time profiles of enavogliflozin in mice after a single oral dose (\(\bullet\)) or repeated oral dosing for 7 days (\(\Circinus\)) and 14 days (\(\blacktriangledown\)). Data are expressed as mean \(\pm\) SD (\(n=5\)).  
Kidney concentrations of enavogliflozin at 1 mg/kg and 3 mg/kg indicated significantly higher concentrations and longer elimination half-lives than plasma enavogliflozin, resulting in high AUC ratios for kidneys to plasma (71.56 \(\pm\) 14.2 at 1 mg/kg and 28.64 \(\pm\) 11.9 at 3 mg/kg) and T\({}_{1/2}\) values (Table 7). The AUC ratio, T\({}_{\rm max}\), and T\({}_{1/2}\) of enavogliflozin in the kidneys were significantly different between the doses of 1 mg/kg and 3 mg/kg. However, the AUC ratio, T\({}_{\rm max}\), and T\({}_{1/2}\) of enavogliflozin in the stomach, small intestine, large intestine, and liver were not significantly different between the two doses. The distribution of enavogliflozin in the lungs and heart was slightly higher than that in the plasma, yielding AUC ratios ranging from 1.672 to 1.954 (Figure 5B,E, Table 7). The distribution of enavogliflozin in the testes and spleen was lower than that in the plasma,  
Figure 5: Plasma and tissue concentration vs. time profiles of enavogliflozin in mice after single oral doses of 1 mg/kg (**A**–**C**) and 3 mg/kg (**D**–**F**). Data are expressed as mean \(\pm\) SD (\(n\) = 6).  
yielding AUC ratios of about 0.5; however, the elimination profiles from the testes and spleen were different. Specifically, the T\({}_{1/2}\) of enavogliflozin in the testes was longer than that of plasma, but the T\({}_{1/2}\) in the spleen was similar to plasma.