RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix-Saposhnikoviae Radix (AR-SR) is a well-known and effective herb pair. Although the compatibility of these two herbs has been widely applied in many traditional Chinese medicine formulas, its potential mechanism still needs to be investigated. AIM OF STUDY: To evaluate the pharmacokinetic profiles of 10 bioactive compounds derived from AR when administrated alone and in combination with SR to rats, aiming to further reveal the impact of SR on AR. MATERIALS AND METHODS: Two groups of male Sprague-Dawley rats received oral administration of AR and AR-SR freeze-dried powder solutions, respectively. UHPLC-QTRAP-MS/MS technology was utilized to perform the pharmacokinetic studies of 10 compounds derived from AR in rat plasma samples. RESULTS: A reliable UHPLC-QTRAP-MS/MS method was established to simultaneously determine the rat plasma concentrations of eight isoflavonoids, referring to calycosin (CAL), calycosin-7-O-ß-D-glucoside (CAL-G), formononetin (FOR), formononetin-7-O-ß-D-glucoside (FOR-G), astrapterocarpan (APC), astrapterocarpan-3-O-ß-D-glucoside (APC-G), astraisoflavan-7-O-ß-D-glucoside (AIF-G) and formononetin-7-O-ß-D-glucuronide (FOR-GN), and two saponins, including astragaloside IV (AS IV) and cycloastragenol (CAG), originating from AR. Following the oral administration of AR, seven isoflavonoids were quickly absorbed but exhibited low plasma concentrations under 17.88 ng/mL except FOR-GN. The latter maintained higher plasma concentration level more than 15 ng/mL for at least 10 h. Besides, for the first time, AS IV was observed with an obvious double-peak phenomenon after administering AR extract, whereas the concentration of CAG was lower than LLOQ before 6 h. When AR and SR were administrated together, the double-peak phenomena of CAL, FOR, APC, AIF-G and FOR-GN were enhanced and there was a significant increase in their values of area under the concentration-time curve (AUC) and mean residence time (MRT) (P < 0.05) while the pharmacokinetic profiles of CAL-G, FOR-G, APC-G, AS IV and CAG stayed almost unchanged (P > 0.05). Moreover, the elimination half-time (t1/2) values of CAL, FOR and APC were significantly elevated, and the clearance rate/bioavailability (CLz/F) for CAL and FOR was reduced (P < 0.05). CONCLUSIONS: SR has the potential to modulate the ADME process of five out of the eight isoflavonoids (CAL, FOR, APC, AIF-G and FOR-GN, except CAL-G, FOR-G and APC-G) originating from AR. This interaction is especially likely to affect the hepatic and intestinal drug disposition of these isoflavonoids, thereby extending the duration of their pharmacological effects, which may subsequently impact the therapeutic efficacy of AR.
RESUMEN
Objective: Paeoniae Radix Rubra (PRR) is a commonly used traditional Chinese medicine with the effects of clearing away heat, cooling the blood, and relieving blood stasis. To 1) elucidate the metabolites and metabolic pathways of PRR and its 14 main constituents in mice and 2) reveal the possible origins of the known effective forms of PRR and their isomers, the metabolism of PRR in mice was systematically studied for the first time. Methods: PRR and its 14 constituents were administered to mice by gavage once a day for seven consecutive days, respectively. All urine and feces were collected during the 7 days of dosing, and blood was collected at 1 h after the last dose. Metabolites were detected and identified using high performance liquid chromatography with diode array detector and combined with electrospray ionization ion trap time-of-flight multistage mass spectrometry (HPLC-DAD-ESI-IT-TOF-MSn). Results: In total, 23, 16, 24, 17, 18, 30, 27, 17, 22, 17, 33, 3, 8, 24, and 31 metabolites of paeoniflorin, albiflorin, oxypaeoniflorin, benzoylpaeoniflorin, hydroxybenzoylpaeoniflorin, benzoyloxypaeoniflorin, galloylpaeoniflorin, lactiflorin, epicatechin gallate, catechin gallate, catechin, ellagic acid, 3,3'-di-O-methylellagic acid, methylgallate, and PRR were respectively identified in mice; after eliminating identical metabolites, a total of 195 metabolites remained, including 8, 11, 25, 17, 18, 30, 27, 17, 21, 17, 1, 2, 8, 20, and 20 newly identified metabolites, respectively. The metabolic reactions of PRR and its 14 main constituents in mice were primarily methylation, hydrogenation, hydrolysis, hydroxylation, glucuronidation, and sulfation. Conclusion: We elucidated the metabolites and metabolic pathways of PRR and its 14 constituents (e.g., paeoniflorin, catechin, ellagic acid, and gallic acid) in mice and revealed the possible origins of the 10 known effective forms of PRR and their isomers. The findings are of great significance to studying the mechanism of action and quality control of PRR.
