Yuan Yongfang, Zhang Hai, Sun Fengfeng, Sun Sen, Zhu Zhenyu, Chai Yifeng
Department of Pharmacy, Shanghai 3rd People׳s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201999, China.
Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
J Ethnopharmacol. 2015 Apr 2;163:31-8. doi: 10.1016/j.jep.2015.01.006. Epub 2015 Jan 14.
Asiatic acid is one of the main components in the herb Centella asiatica, which is a well-known herbal medicine for its excellent pharmacological effects. To enhance the development potentials of asiatic acid as a chemopreventative agent, there is a great need to further understand its biopharmaceutical and pharmacokinetic properties. The aim of this research is to clarify the mechanisms of absorption and metabolism of asiatic acid, and explore its biopharmaceutical and pharmacokinetic properties in rats by using a sensitive and robust HPLC-MS method.
Male Sprague-Dawley rats were randomly assigned to 2 groups and administered with asiatic acid by oral and intravenous administration. Plasma concentrations of asiatic acid were determined at designated points and main pharmacokinetic parameters were estimated. The absorption of asiatic acid was investigated by using Caco-2 cell line absorption model in vitro and rat intestinal perfusion model in situ. The metabolic rate of asiatic acid was investigated by incubating it in rat liver microsome system in vitro. In addition, the solubility of asiatic acid in aqueous solution was also determined by using HPLC-MS method.
The absolute oral bioavailability of asiatic acid is 16.25%. It was found that the permeability of asiatic acid is more than 10(-5) in the Caco-2 cell monolayer and rat intestinal perfusion model, and its main absorption region is the jejunum in rats. The metabolic rate of asiatic acid in rat liver microsomes, t1/2, is 9.493min, which shows that asiatic acid can be metabolized rapidly. The solubility of aisiatic acid was 0.1583mgmL(-1), and its poor solubility will result in low bioavailability.
The asiatic acid in a variety of matrixes was analyzed by using a sensitive and specific HPLC-MS method, and its absolute oral bioavailability in rats was very low. Asiatic acid can be metabolized rapidly in rat liver microsomes, and has good permeability across Caco-2 monolayer cell and rat intestine perfusion. It can be deduced that the low bioavailability of asiatic acid results from poor solubility and rapid metabolism.
积雪草苷是草药积雪草中的主要成分之一，积雪草是一种因具有出色药理作用而闻名的草药。为增强积雪草苷作为化学预防剂的开发潜力，非常有必要进一步了解其生物药剂学和药代动力学特性。本研究的目的是阐明积雪草苷的吸收和代谢机制，并通过使用灵敏且可靠的高效液相色谱-质谱法（HPLC-MS）探索其在大鼠体内的生物药剂学和药代动力学特性。
将雄性Sprague-Dawley大鼠随机分为2组，通过口服和静脉给药的方式给予积雪草苷。在指定时间点测定积雪草苷的血浆浓度，并估算主要药代动力学参数。利用体外Caco-2细胞系吸收模型和原位大鼠肠灌注模型研究积雪草苷的吸收情况。通过在体外大鼠肝微粒体系统中孵育积雪草苷来研究其代谢率。此外，还使用HPLC-MS法测定了积雪草苷在水溶液中的溶解度。
积雪草苷的绝对口服生物利用度为16.25%。发现在Caco-2细胞单层和大鼠肠灌注模型中，积雪草苷的渗透率大于10^(-5)，其主要吸收部位是大鼠的空肠。积雪草苷在大鼠肝微粒体中的代谢率t1/2为9.493分钟，这表明积雪草苷可被快速代谢。积雪草苷的溶解度为0.1583mg/mL(-1)，其低溶解度会导致生物利用度较低。
使用灵敏且特异的HPLC-MS法分析了多种基质中的积雪草苷，其在大鼠体内的绝对口服生物利用度非常低。积雪草苷在大鼠肝微粒体中可快速代谢，并且在Caco-2单层细胞和大鼠肠灌注中具有良好的渗透性。可以推断，积雪草苷的低生物利用度是由低溶解度和快速代谢导致的。
