目的 系统比较愈风宁心片与滴丸在冠心病模型大鼠体内的多成分药动学特征，为该制剂的临床合理选剂型提供实验依据。方法 采用冠状动脉结扎法构建冠心病心肌缺血大鼠模型，先通过超声心动图验证愈风宁心片与滴丸对模型大鼠心功能改善作用；将造模成功大鼠随机分为片剂组与滴丸组，分别ig给予临床等效剂量的愈风宁心片和滴丸，建立并验证超高效液相色谱-三重四极杆串联质谱（UPLC-QQQ-MS/MS）法，同步测定大鼠血浆中3'-羟基葛根素、3'-甲氧基葛根素、大豆苷元、大豆苷、葛根素、葛根素-6''-O-木糖苷、葛根素芹菜糖苷7种异黄酮类成分的含量，采用DAS 2.0软件计算达峰时间（t_max）、最大血药浓度（C_max）、药时曲线下面积（AUC）等药动学参数，对比分析2种剂型的药动学差异。结果 超声心动图结果显示，与模型组相比，愈风宁心片与滴丸组大鼠左心室收缩末期内径、舒张末期内径显著降低，射血分数、缩短分数及心室壁厚度显著升高（P＜0.05、0.01），2种剂型均能显著改善冠心病模型大鼠损伤的心功能。所建立的UPLC-QQQMS/MS方法线性关系良好，精密度、准确度、提取回收率、基质效应及稳定性均符合生物样品分析要求。药动学结果显示，与片剂组相比，滴丸组除大豆苷和葛根素芹菜糖苷外，其余5种异黄酮成分的t_max均显著缩短（P＜0.05、0.01），其中大豆苷元滴丸组t_max仅0.16 h，较片剂组缩短超50%； 3'-羟基葛根素、3'-甲氧基葛根素、大豆苷元的滴丸组C_max显著升高，其中3'-羟基葛根素提升超20倍、3'-甲氧基葛根素提升3倍，大豆苷、葛根素-6''-O-木糖苷、葛根素芹菜糖苷的滴丸组C_max显著降低（P＜0.01）。仅3'-羟基葛根素、大豆苷的滴丸组AUC_0～∞显著高于片剂组（P＜0.05），其余5种成分滴丸组AUC_0～∞均显著降低（P＜0.05、0.01），其中葛根素-6''-O-木糖苷、葛根素芹菜糖苷降低超90%。滴丸组多数成分呈短滞留、快消除特征，3'-羟基葛根素、大豆苷元、葛根素-6''-O-木糖苷的平均滞留时间（MRT）、消除半衰期（t_1/2）显著缩短（P＜0.05、0.01），3'-甲氧基葛根素、大豆苷的滞留及消除相关参数略有升高；且3'-甲氧基葛根素、大豆苷元、大豆苷在2种剂型下均出现血药浓度双峰现象。结论 愈风宁心片与滴丸均能有效改善冠状动脉结扎所致冠心病模型大鼠的心功能损伤。剂型差异可在吸收与消除层面，对7种异黄酮类活性成分的体内处置过程进行差异化调控。基于此药动学差异，滴丸更适用于冠心病急性发作期的快速干预，片剂更适合慢性稳定期的长期维持治疗，为临床根据疾病阶段与治疗需求合理选择剂型提供了实验依据。

Objective To systematically compare the multi-component pharmacokinetic characteristics of Yufeng Ningxin Tablets and Dropping Pills in rat model of coronary heart disease, providing experimental evidence for the rational selection of dosage forms in clinical practice. Methods A rat model of myocardial ischemia due to coronary artery ligation was established. The effects of Yufeng Ningxin Tablets and Dropping Pills on the heart function of the model rats were verified by echocardiography. The rats were randomly divided into tablet and dropping pill groups after successful modeling. The rats were ig administered with the clinically equivalent doses of Yufeng Ningxin Tablets and Dropping Pills, respectively. A UPLC-QQQ-MS/MS method was established and validated to simultaneously determine the contents of seven isoflavone components, including 3'-hydroxypuerarin, 3'-methoxypuerarin, daidzein, daidzin, puerarin, puerarin-6''-O-xyloside, and puerarin apioside, in rat plasma. The pharmacokinetic parameters such as time to peak (t_max), maximum plasma concentration (C_max), and area under the curve (AUC) were calculated using DAS 2.0 software, and the pharmacokinetic differences between the two dosage forms were compared and analyzed. Results Echocardiography results showed that compared with the model group, the left ventricular end-diastolic diameter and end-systolic diameter of the rats in the Yufeng Ningxin Tablet and Dropping Pill groups were significantly reduced, while the ejection fraction, fractional shortening, and ventricular wall thickness were significantly increased (P<0.05, 0.01). Both dosage forms could significantly improve the heart function injury in the coronary heart disease model rats. The established UPLC-QQQ-MS/MS method had good linearity, and the precision, accuracy, extraction recovery, matrix effect, and stability all met the requirements for biological sample analysis. Pharmacokinetic results showed that, compared with the tablet group, the t_max of the five isoflavone components except daidzein and puerarin apioside in the drop pill group were significantly shortened (P<0.05, 0.01), among which the t_max of daidzein in the drop pill group was only 0.16 h, which was shortened by more than 50% compared with the tablet group; the C_max of 3'-hydroxy puerarin, 3'-methoxy puerarin and daidzein in the drop pill group were significantly increased, among which the C_max of 3'-hydroxy puerarin was increased by more than 20 times, and that of 3'-methoxy puerarin was increased by 3 times, while the C_max of daidzein, puerarin-6''-O-xyloside and puerarin apioside in the drop pill group were significantly decreased (P<0.01). Only the AUC_0～∞ of 3'-hydroxy puerarin and daidzein in the drop pill group were significantly higher than those in the tablet group (P<0.05), while the AUC_0～∞ of the other five components in the drop pill group were significantly decreased (P<0.05, 0.01), among which the AUC_0～∞ of puerarin-6''-O-xyloside and puerarin apioside were decreased by more than 90%. Most components in the drop pill group showed the characteristics of short retention and rapid elimination, and the MRT and t_1/2 of 3'-hydroxy puerarin, daidzein and puerarin-6''-O-xyloside were significantly shortened (P<0.05, 0.01), while the retention and elimination related parameters of 3'-methoxy puerarin and daidzein slightly increased. Moreover, 3'- methoxypuerarin, daidzein, and daidzin showed a double-peak phenomenon in plasma concentration in both dosage forms. Conclusion Both Yufeng Ningxin Tablets and Dropping Pills can effectively improve the heart function injury in the rat model of coronary heart disease caused by coronary artery ligation. The differences in dosage forms can differentially regulate the in vivo disposition process of the seven isoflavone active components at the absorption and elimination levels. Based on these pharmacokinetic differences, Dropping Pills are more suitable for rapid intervention during the acute attack of coronary heart disease, while Tablets are more suitable for long-term maintenance treatment during the chronic stable period, providing experimental evidence for the rational selection of dosage forms according to the disease stage and treatment needs in clinical practice.

R969.1;R285.5

国家自然科学基金青年科学基金项目（82505122）；山东省泰山学者青年专家项目（tsqn202103110）；国家中医药管理局科技司共建科技项目（GZY-KJS-SD-2023-093）；山东省数字中药重点实验室项目（22202526）