目的 建立定量测定大鼠血浆中顺式二苯乙烯苷［（cis-2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷（TSG）］与反式二苯乙烯苷（trans-TSG）血药浓度的UPLC-MS/MS方法，系统探究2种异构体在大鼠体内的药动学差异。方法 将40只雄性SD大鼠随机分为4组（每组10只），即cis-TSG ig给药组、cis-TSG尾iv给药组、trans-TSG ig给药组、trans-TSG尾iv给药组。ig组给药剂量为100 mg·kg_-1，尾iv组给药剂量为10 mg·kg_-1；于给药前（0 h）及给药后0.030、0.083、0.160、0.250、0.330、0.500、1.000、2.000、4.000、6.000、8.000、10.000、12.000、24.000 h，通过眼静脉丛采集血样。以虎杖苷为内标，测定上述2个成分在不同时间点的血药浓度；利用DAS 1.0软件计算药动学参数，分析其药动学行为差异。结果 所建立的UPLC-MS/MS方法在专属性、稳定性、准确度与精密度方面均符合体内药物浓度测定的技术要求，且无明显基质效应、提取回收率稳定。药动学结果显示：①给药途径对暴露水平影响显著： 2种成分经iv给药后的血药浓度-时间曲线下面积（AUC）、达峰浓度（C_max）均显著高于ig给药，且达峰时间（t_max）更短，提示iv给药可使药物直接、快速进入体循环；②异构体间暴露差异显著：无论是iv还是ig给药，cis-TSG的AUC、C_max均显著高于trans-TSG（P＜0.05），cis-TSG的消除半衰期（t_1/2）长于trans-TSG［iv（7.03 h vs 2.63 h）、ig（16.90 h vs 8.46 h）］，提示2种异构体在吸收、代谢或分布过程中存在本质差异；③口服生物利用度较低： cis-TSG与trans-TSG的口服绝对生物利用度分别为28.46%、27.35%。结论cis-TSG与trans-TSG在大鼠体内的药动学行为存在显著差异，主要体现为cis-TSG的体内暴露水平更高、消除更缓慢；且2种成分的口服生物利用度均较低。

Objective To establish a UPLC-MS/MS method for the quantitative determination of [cis-2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucosides(TSG)]and trans-TSG in rat plasma and systematically investigate the differences in pharmacokinetic parameters of the two isomers in rats. Methods Forty male SD rats were randomly divided into four groups (10 rats per group), namely the cisTSG ig administration group, the cis-TSG tail iv administration group, the trans-TSG ig administration group, and the trans-TSG tail iv administration group. The ig administration dose was 100 mg·kg^-1, and the tail iv administration dose was 10 mg·kg^-1. Blood samples were collected from the orbital venous plexus at 0 h before administration and at 0.030, 0.083, 0.160, 0.250, 0.330, 0.500, 1.000, 2.000, 4.000, 6.000, 8.000, 10.000, 12.000, and 24.000 h after administration. Polydatin was used as the internal standard to determine the blood drug concentrations of the two components at different time points. The pharmacokinetic parameters were calculated using DAS 1.0 software, and the differences in pharmacokinetic behavior were analyzed. Results The established UPLCMS/MS method met the technical requirements for the determination of drug concentrations in vivo in terms of specificity, stability, accuracy, and precision, and there was no significant matrix effect and the extraction recovery rate was stable. The pharmacokinetic results showed that: ① The administration route significantly affected the exposure level: the area under the blood concentration-time curve (AUC) and peak concentration (C_max) of the two components after iv administration were significantly higher than those after ig administration, and the peak time (t_max) was shorter, indicating that iv administration could directly and rapidly enter the systemic circulation; ② There were significant differences in exposure between the isomers: regardless of iv or ig administration, the AUC and C_max of cis-TSG were significantly higher than those of trans-TSG (P < 0.05), and the elimination half-life (t_1/2) of cis-TSG was longer than that of trans-TSG [iv (7.03 h vs 2.63 h), ig (16.90 h vs 8.46 h)], suggesting that there were essential differences in the absorption, metabolism, or distribution processes of the two isomers; ③ The oral bioavailability was low: the absolute oral bioavailability of cis-TSG and trans-TSG was 28.46% and 27.35%, respectively. Conclusion There were significant differences in the pharmacokinetic behavior of cis-TSG and trans-TSG in rats, mainly manifested as higher in vivo exposure levels and slower elimination of cis-TSG. The oral bioavailability of both components was low.

R969.1;R284.1

天津市教委重点项目（2024ZD001）