Pharmacokinetic Characterization of the Gastrointestinal Acute Radiation Syndrome Mitigator YK-4-250 in Male and Female Mice Under Non-Irradiated and Partial Body Irradiation Conditions

The therapeutic evaluation of novel small-molecule candidates requires a comprehensive understanding of their pharmacokinetic (PK) profiles under both baseline physiological conditions and pathophysiological stress states, such as radiation exposure. This study evaluates YK-4-250, a long acting Tempol-conjugated angiotensin receptor blocker (TCARB) being developed to treat gastrointestinal acute radiation syndrome (GI-ARS). Specifically, the study characterizes YK-4-250's non-compartmental PK profile following oral administration of 20 and 40 mg/kg doses to male and female, non-irradiated and irradiated C57BL/6 mice. Male and female mice were stratified into non-irradiated and partial-body irradiation (PBI) at the LD _50/30 (14.6 Gy). Serial plasma concentrations were analyzed over a 72-hour timeline using non-compartmental analysis (NCA) to determine key parameters (C _max , T _max , AUC, t _1/2 , CL, and Vz). In the non-irradiated state, oral absorption was rapid, with an identical time-to-peak (T _max = 1.0 hr) across all cohorts. Dose escalation from 20 to 40 mg/kg in non-irradiated mice yielded a supra-linear expansion in AUC _last (3.76 to 12.53 µg∙hr/mL in males and 6.45 to 18.99 µg∙hr/mL in females), indicating saturation of baseline clearance pathways. Exposure to radiation fundamentally altered these kinetic profiles. At the 20 mg/kg dose threshold post-irradiation, a significant sex-based divergence emerged with irradiated females exhibiting significantly higher and prolonged exposure than irradiated males This resulted in doubling total projected exposure (AUC _inf = 8.80 vs.4.37 µg∙hr/mL) due to a 50.1% reduction in systemic clearance and an 85.2% prolongation of elimination half-life (t _1/2 = 7.81 vs. 3.12 hr). However, at 40 mg/kg of YK-4-250, irradiation acted as a "physiological equalizer," eliminating the exposure gaps. Total exposure (AUC _inf approximately 22 µg∙hr/mL) and clearance converged to nearly equivalent values between the males and females. Concurrently, both sexes experienced a significant, extension of terminal half-life (22.51 hr in males and 18.75 hr in females). The primary differentiating features at 40 mg/kg under radiation were a significant, sex-specific delay in female absorption (T _max doubled from 3.0 hr in males to 6.0 hr in females) and a 19.2% higher apparent volume of distribution (Vz) in males. Altogether, these findings suggest that radiation exposure can compromise systemic clearance mechanisms in both male and female mice treated with YK-4-250, potentially via the downregulation of hepatic phase I/II metabolic pathways and altered gastrointestinal transit, which may necessitate precise adaptive dosing regimens for radiation-mitigative or protective indications in higher species.