## 1 Introduction
Based on these clinical outcomes of cardiorenal protection, the American Diabetes Association recommends that SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists can be used--in combination with metformin--as first-line therapy for diabetic patients at high risk of heart failure, cardiovascular disease, and chronic kidney disease [20]. Moreover, recent studies have reported these cardioprotective and nephoprotective effects regardless of the presence of diabetes [20; 21]. Canagliflozin has been shown to protect against cisplatin-induced acute kidney injury by activating AMPK (adenosine monophosphate-activated protein kinase) and inducing autophagy in renal proximal tubular cells [21]. Empagliflozin protected against methotrexate-induced renal toxicity via suppression of oxidative stress and inflammation in male rats [22]. Empagliflozin and dapagliflozin inhibited mTOR1 (mechanistic target of rapamycin complex 1) and HIF-\(\alpha\) (hypoxia-inducible factor-1\(\alpha\)), consequently showing protective effects in glomerular injury in lupus nephritis. Relevant clinical trials confirmed the acceptable safety profile of SGLT2 inhibitors for the treatment of lupus nephritis [23; 24]. Considering the higher distribution of SGLT2 inhibitors to the kidneys and their mechanism of action in renal proximal tubular cells, the nephoprotective effects of SGLT2 inhibitors suggest their potential as promising therapeutics for acute kidney injury through reducing oxidative stress, increasing inflammatory mediators, and enhancing apoptotic reactions in the renal tissue [22]. Based on SGLT2 expression in retinal pericytes [25; 26], SGLT2 inhibitors exert therapeutic effects by reducing glucose entry into pericytes, reducing oxidative stress, and restoring insulin signaling [25; 26; 27]. [PERSON] et al. investigated the ocular and plasma pharmacokinetics of enavggliflozin in rabbits using enavggliflozin ophthalmic solution to evaluate its therapeutic potential for the treatment of diabetic retinopathy [25]. Additionally, enavggliflozin significantly decreased nanoplastic-induced premature endothelial senescence and dysfunction caused by upregulated cardiovascular SGLT2 [28]. It also improved vascular function by decreasing reactive oxygen species and upregulating endothelial nitric oxide synthase expression [28]. The study suggested that enavggliflozin improves vascular function through SGLT2 inhibition and inhibits the inflammatory response; enavggliflozin needs to be evaluated as a potential agent for the prevention of vascular aging-related disorders and cardiovascular disease caused by nanoplastic contaminants [29]. [PERSON] et al. evaluated the anti-obesity effect of enavggliflozin in naturally obese dogs. Body weight, body fat percentage, and fat thickness were significantly reduced in the enavggliflozin-treated group without affecting food consumption compared to the obese control group [30]. Taken together, the therapeutic potency of enavggliflozin could be expanded to include acute or chronic kidney injury, cardiovascular disease, retinopathy, and an anti-obesity effect in addition to T2 DM treatment. In these cases, the expression of SGLT2 and tissue distribution kinetics of enavggliflozin could be important factors for the therapeutic expansion of this drug since its mechanism of action, which was reported as reduced oxidative stress, increased inflammatory mediators, and enhanced apoptotic reactions, is not tissue- or site-specific. Therefore, we aimed to examine the pharmacokinetic characteristics of enavggliflozin, including differences between fasted and fed states and between single and repeated doses, which can be useful information to find a dose regimen for pharmacology study and the pharmacology-pharmacodynamic relationship regarding the new therapeutic efficacy of enavggliflozin. We also aimed to investigate dose dependency in the tissue distribution of enavggliflozin in mice.