Pharmacokinetics, plasma protein binding, and metabolism of a potential natural chemosensitizer from Marsdenia tenacissima in rats. (5th December 2021)

• Record Type: Journal Article
• Authors: Xie, Bin; Jiang, Shi-Qi; Shen, Xiao-Ling; Wu, Hui-Qin; Hu, Ying-Jie
• Is Part Of: Journal of ethnopharmacology. Volume 281(2021)
• Publication Date: 2021-12-05
• Subjects: Marsdenia tenacissima -- 11α-O-2-methybutyryl-12β-O-Tigloyl-tenacigenin B -- Chemosensitizer -- Pharmacokinetics -- Plasma protein binding -- Metabolism; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2021.114544
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: Marsdenia tenacissima (Roxb.) Wight et Arn is a medicinal plant mainly distributed in southwest China. It is used in folk medicine for the treatment of tumors and is synergistic with chemotherapies. In our previous study, 11α- O -2-methybutyryl-12β- O -tigloyl-tenacigenin B (MT2), a main steroid aglycone isolated from the total aglycones of M. tenacissima, significantly enhanced the in vivo antitumor effect of paclitaxel in mice bearing human tumor xenografts, showing its potential as a chemosensitizer. However, the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 remain unclear. Aim of the study: To elucidate the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 in rats. Materials and methods: MT2 in rat plasma and phosphate-buffered saline was quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method, while the MT2 metabolites in rat liver microsomes were analyzed using UPLC-triple time-of-flight MS/MS. Results: For intravenously administered MT2, the maximum plasma concentration and the area under the plasma concentration-time curve indicated dose dependency, while the elimination half-life time, the mean residence time, apparent volume of distribution and total apparent clearance values remained relatively unchanged in both the 5 mg/kg and 10 mg/kg groups. For orally administered MT2, the bioavailability was 1.08–1.11%. In rat plasma, MT2 exhibited a protein binding rate of 93.84–94.96%. In rat liver microsomes, MT2 was metabolized by oxidation alone or in combination with demethylation, and five MT2 metabolites were identified. Conclusion: MT2 has low oral bioavailability and a high plasma protein binding rate in rats. After administration, MT2 is transformed into oxidative metabolites in the liver. To achieve a high blood concentration of MT2, it should be administered intravenously. These findings would serve as a reference for further MT2-based pharmacological study and drug development. Graphical abstract: Image 1 Highlights: The MT2 pharmacokinetic profiles and plasma protein binding rates were determined. MT2 metabolites in rat liver microsomes and metabolic pathways were analyzed. MT2 had low oral bioavailability and a high plasma protein binding rate.