Pharmacokinetics and Single-Time-Point Organ Distribution of the SGLT2 Inhibitor Dapagliflozin After Cardiac Irradiation in Rats: An Exploratory Study

Background: Cardiac stereotactic body radiation therapy (SBRT) and dapagliflozin (DAPA) act on overlapping electrophysiological pathways, but whether cardiac irradiation alters DAPA disposition is unknown. Methods: Male Sprague-Dawley rats received sham irradiation, 2-Gy whole-heart irradiation, or 12-Gy irradiation of a central 1.0 × 1.0 cm cardiac field, followed by oral DAPA (3 mg/kg) 2 h (2 h post-RT) or 24 h (24 h post-RT) later. Plasma DAPA was measured by HPLC-UV over 240 min for non-compartmental analysis (n = 6/group); heart, liver, and kidney concentrations were measured once, 4 h after dosing (n = 5/group). Groups were compared by Welch ANOVA with Games–Howell tests (Kruskal–Wallis for Tmax). Results: AUC0–240 did not differ significantly among groups (247–305 min·µg/mL; p = 0.66), although confidence intervals were wide. Tmax was numerically longer in the 2-Gy 2 h post-RT group (190 ± 24 vs. 100 ± 31 min), but the Kruskal–Wallis test was not significant (p = 0.090). Terminal-phase parameters (t1/2, MRT, CL/F, Vss/F) were treated as exploratory because 40–63% of AUC0–∞ was extrapolated; none differed significantly. At 4 h, renal DAPA was lower in the 12-Gy 24 h post-RT group (23.52 ± 2.40 vs. 56.09 ± 2.45 µg/g; p < 0.001), and hepatic DAPA was higher in the 2-Gy 24 h post-RT group (17.32 ± 3.17 vs. 6.67 ± 1.58 µg/g; p = 0.003); cardiac concentrations did not differ significantly from control. Conclusions: In this exploratory study, cardiac irradiation did not produce a detectable change in early systemic DAPA exposure. The single-time-point organ differences are hypothesis-generating and do not establish altered tissue exposure; whether DAPA timing relative to cardiac SBRT matters clinically requires dedicated study.