Abstract
We previously reported that duodenal administration of the natural flavone acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.
Highlights
These studies suggest that acacetin may act as a highly potential drug candidate for treating Atrial fibrillation (AF) by blocking multiple atrial ion channels
Our results demonstrated that the phosphate sodium prodrug of acacetin was highly water-soluble, could be converted into acacetin in vivo, and can effectively terminate AF induced by vagal nerve stimulation in beagle dogs
The results indicate that acacetin prodrug cannot inhibit the cardiac ion channels directly like the parent drug acacetin
Summary
These studies suggest that acacetin may act as a highly potential drug candidate for treating AF by blocking multiple atrial ion channels. The poor water solubility of acacetin is a key challenge in developing clinically usable forms. To improve the water solubility of parent drug in the prodrug design, the conjugation of some polar functional groups, e.g. carboxylic, hydroxyl, amine, phosphate, carbonyl, or thiol groups directly or through a linker motif, is a popular choice[15,16,17]. The present study synthesized a water-soluble prodrug of acacetin by introducing a phosphate group for intravenous use and investigated whether the prodrug could be converted into the parent compound acacetin and terminate experimental AF in beagle dogs. Our results demonstrated that the phosphate sodium prodrug of acacetin was highly water-soluble, could be converted into acacetin in vivo, and can effectively terminate AF induced by vagal nerve stimulation in beagle dogs
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