Metabolic and Pharmacokinetic Investigation of Ilexsaponin A1 in Normal and Antibiotic-treated Rats

Background Ilexsaponin A 1 (IA 1 ) is a bioactive triterpene saponin derived from natural medicinal plants. IA 1 exhibits anti-inflammatory and proangiogenic activities and improves intestinal barrier function. It has been reported that IA 1 could be metabolized into a dominant metabolite, ilexgenin A (IA) by β-glucosidase enzymes in intestinal microflora. Materials and Methods Herein, an accurate, sensitive, and selective method based on ultra-performance liquid chromatography coupled with mass spectrometry was established to simultaneously profile the metabolism and pharmacokinetic behaviors of IA 1 in normal and antibiotic-treated rat plasma after intragastric administration of IA 1 . The precursor-to-product ion pairs of IA and IA 1 were m/ z 501.32↓439.32 and m/ z 663.38↓501.32, respectively. For method validation, the specificity, matrix effect, accuracy, precision, and stability of the pharmacokinetic study were measured, and a calibration curve was created. The collaborative pharmacological target pathways of IA 1 and its metabolite IA were investigated using network pharmacology tools. Results The validated analytical method was successfully utilized to investigate the pharmacokinetics of IA 1 in normal and antibiotic-treated rats. The bioavailability of IA 1 and conversion from IA 1 to IA were significantly inhibited by antibiotic-treated rats after oral administration of IA 1 . Fragment ions at m/z 483.3155, 455.3159, 439.3233, 421.3136, 395.3362, 152.9952, 113.0256, and 71.0531 were characteristic of the IA 1 moiety. IA 1 was metabolized in rat plasma by biotransformation routes involving deglycosylation, decarboxylation, isomerization, hydrogenation, dehydrogenation, and oxidation. Considering database analysis, IA and IA 1 play synergistic role in common pharmacological pathways, such as hypertrophic cardiomyopathy and dilated cardiomyopathy. Conclusion The experiments illustrated that β-glucosidase activity inhibited by antibiotics suppressed the hydrolysis reaction of IA 1 in the intestinal tract. IA 1 and IA play a synergistic role in exerting effects.