Jiang Jun, Feng Liang, Sun E, Li Haotian, Cui Li, Jia Xiaobin
Affiliated Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu Province, China; Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, 100# Shizi Road, Nanjing, 210028, Jiangsu Province, China.
Drug Test Anal. 2015 Apr;7(4):309-19. doi: 10.1002/dta.1672. Epub 2014 Jun 16.
The isomers, although of similarly chemical structures, have different pharmacological activities due to their metabolic processes in vivo. Central-icaritin (c-IT) and icaritin (IT) are isomers and major bioactive aglycones of the Herba Epimedii. In this study, we found that the anti-osteoporotic effect of c-IT was stronger than IT on bone structural changes in osteoporotic rats evaluated by Micro-μCT with the parameters of bone mineral density (BMD), bone mineral content (BMC), tissue mineral content (TMC), and tissue mineral density (TMD). c-IT treatment significantly increased the bone microarchitecture, compared with IT (p < 0.05). In order to explain their differences in anti-osteoporosis, the metabolic profiling and pathways of c-IT and IT in the plasma, bile, urine, and faeces of ovariectomized (OVX) rats were investigated by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF-MS) after oral administration of c-IT or IT (80 mg/kg). Finally, 59 metabolites of c-IT and 43 metabolites of IT were identified by elucidating their corresponding quasimolecular ions and fragment ions. IT could be quickly absorbed into blood and reached a maximum plasma concentration, and then be rapidly conversed to its glucuronidation metabolites, most of which were excreted out by urine. Interestingly, the absorbed and conjugated speeds of c-IT were slower than IT. The metabolic processes of c-IT existed enterohepatic circulation, which decreased the metabolism and excretion rate of c-IT, and prolonged the anti-osteoporosis effect. Our findings provided evidence on the difference on metabolic profiles of c-IT and IT in osteoporotic rats, which might shed new lights on improving anti-osteoporotic effects of IT and c-IT.
这些异构体虽然化学结构相似，但由于它们在体内的代谢过程不同，因而具有不同的药理活性。中紫花淫羊藿素（c-IT）和淫羊藿素（IT）是淫羊藿的异构体和主要生物活性苷元。在本研究中，我们发现，通过显微μCT以骨密度（BMD）、骨矿物质含量（BMC）、组织矿物质含量（TMC）和组织矿物质密度（TMD）为参数评估，c-IT对骨质疏松大鼠骨结构变化的抗骨质疏松作用比IT更强。与IT相比，c-IT治疗显著改善了骨微结构（p < 0.05）。为了解释它们在抗骨质疏松方面的差异，在口服给予c-IT或IT（80 mg/kg）后，通过超高效液相色谱四极杆飞行时间质谱（UPLC-QTOF-MS）研究了去卵巢（OVX）大鼠血浆、胆汁、尿液和粪便中c-IT和IT的代谢谱及代谢途径。最终，通过阐明它们相应的准分子离子和碎片离子，鉴定出了59种c-IT的代谢产物和43种IT的代谢产物。IT能够迅速被吸收进入血液并达到最大血浆浓度，然后迅速转化为其葡萄糖醛酸化代谢产物，其中大部分通过尿液排出。有趣的是，c-IT的吸收和结合速度比IT慢。c-IT的代谢过程存在肠肝循环，这降低了c-IT的代谢和排泄速率，并延长了其抗骨质疏松作用。我们的研究结果为骨质疏松大鼠中c-IT和IT代谢谱的差异提供了证据，这可能为提高IT和c-IT的抗骨质疏松作用提供新的思路。
