Time-dependent pharmacokinetic changes and renal SGLT2 expression alterations of dapagliflozin under high-altitude hypoxia in diabetic rats

Objective This study investigated the time-dependent effects of high-altitude hypoxia on the pharmacokinetics (PK), renal sodium-glucose cotransporter 2 (SGLT2) expression, and glycemic response to dapagliflozin in type 2 diabetes mellitus (T2DM) rats. Methods T2DM was induced in male Wistar rats via high-fat diet and low-dose streptozotocin. In the acute study, rats received a single oral dose of dapagliflozin (1 mg/kg) after a 3-day exposure to normoxia or simulated 6000 m hypoxia. In the chronic study, rats received daily dapagliflozin (1 mg/kg) during a 14-day period under normoxia or chronic hypoxia. Plasma dapagliflozin concentrations were determined by UPLC-MS/MS. Fasting blood glucose was monitored serially, and renal cortical SGLT2 protein levels were quantified by ELISA at study endpoint. Individual exposure–response relationships were assessed by Spearman correlation. Results Acute hypoxia caused a dramatic PK perturbation: AUC 0-t and C max increased by 6.58-fold and 5.06-fold, respectively, compared with acute normoxia (all p < 0.01). Chronic hypoxia produced a significant but attenuated effect: AUC 0-t and C max increased by 2.11-fold and 1.69-fold, respectively (all p < 0.01), representing an approximately 70% reduction in the magnitude of PK change under chronic versus acute exposure. Chronic hypoxia was also associated with significantly attenuated early glycemic reduction at days 4 and 7 ( p < 0.01), though fasting blood glucose levels converged by day 14. Although these observations were temporally associated, a direct causal link is not supported, as SGLT2 was measured only at day 14 whereas glycemic differences emerged earlier (days 4–7). Pooled analysis showed no significant correlation between dapagliflozin exposure and day-14 fasting blood glucose, whereas group-stratified analysis revealed a significant negative correlation between AUC 0-t and day-14 fasting blood glucose in normoxic rats only. Conclusion Dapagliflozin pharmacokinetics undergo time-dependent adaptation under high-altitude hypoxia. Exposure–response analysis suggested a hypoxia-induced dissociation between dapagliflozin exposure and glycemic response. These findings underscore the need for dedicated clinical PK–PD monitoring in high-altitude populations and provide a descriptive framework for future mechanistic and translational investigations.