Identification and Pharmacokinetic Studies on Complanatuside and Its Major Metabolites in Rats by UHPLC-Q-TOF-MS/MS and LC-MS/MS

The metabolic and pharmacokinetic studies on complanatuside, a quality marker of a Chinese materia medicatonic, Semen Astragali Complanati, were carried out. The UHPLC-Q-TOF/MS (ultra-high performance liquid chromatography coupled with electrospray ionization tandem quadrupole-time-of-flight mass spectrometry) method was applied to identify the metabolites of complanatuside in rat plasma, bile, stool, and urine after oral administration at the dosage of 72 mg/kg. Up to 34 metabolites (parent, 2 metabolites of the parent drug, and 31 metabolites of the degradation products) were observed, including processes of demethylation, hydroxylation, glucuronidation, sulfonation, and dehydration. The results indicated glucuronidation and sulfonation as major metabolic pathways of complanatuside in vivo. Meanwhile, a HPLC-MS method to quantify complanatuside and its two major metabolites—rhamnocitrin 3-O-β-glc and rhamnocitrin—in rat plasma for the pharmacokinetic analysis was developed and validated. The Tmax (time to reach the maximum drug concentration) of the above three compounds were 1 h, 3 h, and 5.3 h, respectively, while the Cmax (maximum plasma concentrations)were 119.15 ng/mL, 111.64 ng/mL, and 1122.18 ng/mL, and AUC(0-t) (area under the plasma concentration-time curve) was 143.52 µg/L·h, 381.73 µg/L·h, and 6540.14 µg/L·h, accordingly. The pharmacokinetic characteristics of complanatuside and its two metabolites suggested that complanatuside rapidly metabolized in vivo, while its metabolites—rhamnocitrin—was the main existent form in rat plasma after oral administration. The results of intracorporal processes, existing forms, and pharmacokinetic characteristics of complanatuside in rats supported its low bioavailability.

[1]  Ningping Tao,et al.  Naringenin, a common flavanone, inhibits the formation of AGEs in bread and attenuates AGEs-induced oxidative stress and inflammation in RAW264.7 cells. , 2018, Food chemistry.

[2]  K. Deng,et al.  Rapid qualitative and quantitative analyses of eighteen phenolic compounds from Lycium ruthenicum Murray by UPLC-Q-Orbitrap MS and their antioxidant activity. , 2018, Food chemistry.

[3]  Hua Zhou,et al.  Metabolites profile of Gualou Xiebai Baijiu decoction (a classical traditional Chinese medicine prescription) in rats by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. , 2018, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[4]  Xingbin Yang,et al.  Antihypertensive effects of Tartary buckwheat flavonoids by improvement of vascular insulin sensitivity in spontaneously hypertensive rats. , 2017, Food & function.

[5]  J. Terao Factors modulating bioavailability of quercetin‐related flavonoids and the consequences of their vascular function , 2017, Biochemical pharmacology.

[6]  Rosa Pérez-Gregorio,et al.  Wine Flavonoids in Health and Disease Prevention , 2017, Molecules.

[7]  Ping Xu,et al.  Activating AKT to inhibit JNK by troxerutin antagonizes radiation‐induced PTEN activation , 2017, European journal of pharmacology.

[8]  R. Ranjan,et al.  A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice , 2016, PloS one.

[9]  E. Lephart Skin aging and oxidative stress: Equol’s anti-aging effects via biochemical and molecular mechanisms , 2016, Ageing Research Reviews.

[10]  Yanhui Li,et al.  Simultaneous Determination of Formononetin, Calycosin and Rhamnocitrin from Astragalus Complanatus by UHPLC-MS-MS in Rat Plasma: Application to a Pharmacokinetic Study. , 2016, Journal of chromatographic science.

[11]  L. Pang,et al.  Quantification of complanatoside A in rat plasma using LC-MS/MS and its application to a pharmacokinetic study. , 2016, Biomedical chromatography : BMC.

[12]  Ke Lan,et al.  A chemical profiling strategy for semi-quantitative analysis of flavonoids in Ginkgo extracts. , 2016, Journal of pharmaceutical and biomedical analysis.

[13]  Xiaofeng Zhou,et al.  Anti-proliferative Constituents from Selaginella moellendorffii , 2016, Natural product communications.

[14]  Yong Chen,et al.  Identification of in vivo and in vitro metabolites of 4,5-dimethoxycanthin-6-one by HPLC-Q-TOF-MS/MS. , 2016, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[15]  G. Murtaza,et al.  Anti-Aging Potential of Phytoextract Loaded-Pharmaceutical Creams for Human Skin Cell Longetivity , 2015, Oxidative medicine and cellular longevity.

[16]  N. Al-Harbi,et al.  Hepato-protective effect of rutin via IL-6/STAT3 pathway in CCl4-induced hepatotoxicity in rats , 2015, Biological Research.

[17]  J. Geleijnse,et al.  Supplementation of the Pure Flavonoids Epicatechin and Quercetin Affects Some Biomarkers of Endothelial Dysfunction and Inflammation in (Pre)Hypertensive Adults: A Randomized Double-Blind, Placebo-Controlled, Crossover Trial. , 2015, The Journal of nutrition.

[18]  Huidi Jiang,et al.  Metabolism of flavonoids in human: a comprehensive review. , 2014, Current drug metabolism.

[19]  X. Yao,et al.  Five new flavonoid glycosides from Nervilia fordii , 2013, Journal of Asian natural products research.

[20]  C. Biliaderis,et al.  Simultaneous determination of phenolic acids and flavonoids in rice using solid-phase extraction and RP-HPLC with photodiode array detection. , 2012, Journal of separation science.

[21]  A. Buciński,et al.  Quercetin from shallots (Allium cepa L. var. aggregatum) is more bioavailable than its glucosides. , 2008, The Journal of nutrition.

[22]  Y. Tzeng,et al.  Anti-oxidant and inflammatory mediator's growth inhibitory effects of compounds isolated from Phyllanthus urinaria. , 2008, Journal of ethnopharmacology.

[23]  K. Hong,et al.  Biotransformation of soybean isoflavones by a marine Streptomyces sp. 060524 and cytotoxicity of the products , 2008 .

[24]  Yuping Wang,et al.  [Determination of complanatoside A in semen Astragali complanati by HPLC]. , 2005, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[25]  C. Yang,et al.  Cytoprotective effects of Glycyrrhizae radix extract and its active component liquiritigenin against cadmium-induced toxicity (effects on bad translocation and cytochrome c-mediated PARP cleavage). , 2004, Toxicology.