RESUMO
Sennoside B is a specific dianthrone compound extracted from senna, which is widely used as a stimulant laxative but has potential side effects. This study aimed to obtain the metabolic and pharmacokinetic data of sennoside B. The metabolic profiles of sennoside B were obtained from rat plasma, urine, bile and feces by an ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). As a result, 14 metabolites were structurally identified and the proposed metabolic pathways of sennoside B included hydrolysis to aglycones, release of rhein-type anthrone, and extensive conjugation. As the only compound detected in the plasma samples after intravenous and intragastric administrations, the prototype was selected as the plasma marker in the pharmacokinetic study. A simple and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the quantitation of sennoside B in rat plasma. The linear range of sennoside B was 5-1000â¯ng/mL (R2 ≥ 0.991) and the lowest limit of quantification (LLOQ) was 5â¯ng/mL. The intra- and inter- precisions of the assay were less than 10%, whereas accuracy ranged from 85.80% to 103.80%. The extraction recovery, matrix effect and stability of sennoside B were within acceptable limits. The established method was well validated and successfully applied to the pharmacokinetic study of sennoside B. The oral absolute bioavailability of sennoside B was calculated as 3.60% and the value apparent volume of distribution of intravenous and intragastric administrations were 32.47⯱â¯10.49â¯L/kg and 7646⯱â¯1784â¯L/kg, respectively. The maximum plasma concentrations were 212.6⯱â¯50.9⯵g/L and 14.06⯱â¯2.73⯵g/L for intravenous and intragastric dosing groups, respectively. According to the current results of pharmacokinetic and metabolic profiling studies, metabolites with high abundance in tissues would be the next object in the pharmacokinetic study of sennoside B.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Senosídeos/farmacocinética , Animais , Disponibilidade Biológica , Limite de Detecção , Masculino , Ratos , Ratos Sprague-Dawley , Senosídeos/análise , Espectrometria de Massas em TandemRESUMO
Rhubarb is a popular food in Europe with laxative properties attributed to anthraquinones. Long term usage of rhubarb anthraquinones has been linked to colonic toxicity, including the formation of melanosis coli, which is associated with increased risk of colon cancer. The major purgative anthraquinone in rhubarb is thought to be sennoside A, which is metabolised by colonic microflora. Here, we sought to identify the toxic metabolite responsible for melanosis coli in rats dosed with rhubarb anthraquinones for up to 90 days. Three metabolites were detected in rat faeces using HPLC. Of these, rhein was identified as the metabolite that accumulated most over time. Fecal flora from treated rats were capable of greater biotransformation of sennoside A to rhein compared to that from control rats. Cell culture experiments suggested that apoptosis and autophagy induced by rhein is the likely mechanism of chronic toxicity of rhubarb anthraquinones.