Wang Ting, Leng Dan-Dan, Gao Fei-Fei, Jiang Chun-Jie, Xia Yu-Feng, Dai Yue
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
Department of Chinese Materia Medica Analysis, China Pharmaceutical University, Nanjing 210009, China.
Chin J Nat Med. 2014 Dec;12(12):943-51. doi: 10.1016/S1875-5364(14)60138-2.
To develop a simple and highly sensitive high performance liquid chromatography with electrospray ionization mass spectrometric (LC-ESI-MS) method for the simultaneous determination of madecassoside and its major metabolite madecassic acid in rat plasma, and compare the pharmacokinetics of the two compounds in normal and collagen-induced arthritis (CIA) rats. Glycyrrhetinic acid was used as the internal standard (IS). Chromatographic separation was accomplished on an Inertsil ODS-3 column, using a gradient elution with the mobile phase composed of acetonitrile and water acidified with 0.1% (V/V) formic acid. Detection was achieved by ESI-MS under the negative selected ion monitoring (SIM) mode. In normal and CIA rats, madecassoside (30 mg·kg(-1)) was orally administered for 21 consecutive days from the day of arthritis onset. For madecassoside, the linear range was 10-1 000 ng·mL(-1) with the square regression coefficient (r) of 0.998 9, while for madecassic acid, the linear range was 10-500 ng·mL(-1) with the square regression coefficient (r) of 0.996 1. The lower limit of quantification was 10 ng·mL(-1) for both analytes. The intra- and inter-day precision ranged from 1.78% to 13.42% for madecassoside and 2.30% to 14.90% for madecassic acid, and the accuracy was between -0.95% and 6.30% for madecassoside and between -1.48% and 5.34% for madecassic acid. The average recoveries of madecassoside, madecassic acid and IS from spiked plasma samples were > 81%. The developed method was successfully applied to the pharmacokinetic study of madecassoside and madecassic acid in rats after an oral administration of madecassoside. During initial 7 days of dosing, the cmax and AUC of madecassoside were greatly decreased and Vd/F was markedly increased in CIA rats, and no significant difference was observed on the first day of dosing. In contrast, the T1/2, cmax and AUC of madecassic acid were significantly increased, and Ke of madecassic acid was greatly decreased in CIA rats compared with normal rats. Along with repeated administration of madecassoside, the differences of pharmacokinetic parameters of both madecassoside and madecassic acid between CIA and normal rats gradually subsided. The pharmacokinetic characteristics of both madecassoside and madecassic acid in rats were significantly altered by arthritis status, and the differences of pharmacokinetic parameters between arthritis and normal rats coincide with the severity of arthritis.
建立一种简单、高灵敏度的高效液相色谱-电喷雾电离质谱联用（LC-ESI-MS）法，用于同时测定大鼠血浆中积雪草苷及其主要代谢产物羟基积雪草苷，并比较这两种化合物在正常大鼠和胶原诱导性关节炎（CIA）大鼠中的药代动力学。以甘草次酸作为内标（IS）。采用Inertsil ODS-3色谱柱进行色谱分离，流动相为乙腈和用0.1%（V/V）甲酸酸化的水，进行梯度洗脱。通过ESI-MS在负离子选择离子监测（SIM）模式下进行检测。在正常大鼠和CIA大鼠中，从关节炎发病当天起连续21天口服积雪草苷（30 mg·kg⁻¹）。对于积雪草苷，线性范围为10 - 1000 ng·mL⁻¹，平方回归系数（r）为0.998 9；对于羟基积雪草苷，线性范围为10 - 500 ng·mL⁻¹，平方回归系数（r）为0.996 1。两种分析物的定量下限均为10 ng·mL⁻¹。积雪草苷的日内和日间精密度范围为1.78%至13.42%，羟基积雪草苷为2.30%至14.90%；积雪草苷的准确度在-0.95%至6.30%之间，羟基积雪草苷在-1.48%至5.34%之间。加标血浆样品中积雪草苷、羟基积雪草苷和内标的平均回收率均>81%。所建立的方法成功应用于口服积雪草苷后大鼠体内积雪草苷和羟基积雪草苷的药代动力学研究。在给药的最初7天内，CIA大鼠中积雪草苷的Cmax和AUC大幅降低，Vd/F显著增加，给药第一天未观察到显著差异。相比之下，CIA大鼠中羟基积雪草苷的T1/2、Cmax和AUC显著增加，Ke大幅降低。随着积雪草苷的重复给药，CIA大鼠和正常大鼠中积雪草苷和羟基积雪草苷的药代动力学参数差异逐渐减小。大鼠中积雪草苷和羟基积雪草苷的药代动力学特征因关节炎状态而显著改变，关节炎大鼠和正常大鼠之间药代动力学参数的差异与关节炎的严重程度一致。
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