Mammary and brain pharmacokinetics of licochalcone A after oral and intravenous administration: implications for breast cancer prevention and interception

Introduction Licochalcone A (LicA), a prenylated chalcone from Glycyrrhiza inflata , shows promising anti-tumor activity in breast cancer models, but translation is limited by poor bioavailability and rapid systemic clearance. Oral delivery is the clinically favored route for long-term use of breast cancer prevention drugs in women at elevated risk of developing breast cancer. We report the first validated quantification of LicA in mammary tissue in a prevention context and the first characterization of brain distribution under intact blood-brain barrier (BBB) conditions for intercepting brain metastasis. Methods Formulations spanning aqueous (F07), lipid-based (L05), surfactant-rich (L13) and co-solvent (L022, L024) systems were selected by solubility screening and simulated gastrointestinal re-dispersibility. Eight independent pharmacokinetic studies were conducted across two species. Plasma, mammary, brain, and liver were quantified. Results and Discussion Subcutaneous L022 (80 mg/kg/day, 28 days) that suppressed tumor growth in mice, presented a trough plasma LicA of 68 ng/mL (IQR 35–105), below in vitro -effective thresholds. Oral L024 in mice was rapidly absorbed (T max 0.25–0.5 h, plasma C max 817 ng/mL) and achieved mammary (C max 1,093 ng/g), with tissue-to-plasma partitioning (Kp) > 1 by every metric at 100 mg/kg. Brain-to-plasma Kp remained 0.3–0.5 after oral dosing but exceeded 1 from 1 h after intravenous dosing, reaching 3.92 at 8 h, while brain C max rose from 378 to 9,925 ng/g. Dose-normalized plasma exposure was 37-fold lower after oral than intravenous administration and brain exposure fell almost proportionally, by 27.5-fold. We interpret this as indicating that limited oral brain exposure reflects pre-systemic loss rather than restricted BBB transfer, although transfer kinetics were not measured directly. In rats, F07 was constrained by low drug-loading, while L05 and L13 achieved higher loading and prolonged T 1/2 but were only characterized in plasma. L13 was not tolerated intravenously in pre-study tolerability assessment, and L05 was not advanced on formulation-development grounds rather than on pharmacokinetic performance. L024 was tolerated by both routes and was the only formulation for which tissue distribution data. It was selected as the lead candidate for chronic evaluation on the basis of tissue distribution data and dual-route tolerability. L024s short half-life predicts a low once-daily steady-state trough, addressable by divided dosing.