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延胡索乙素不同给药方式在神经病理痛模型大鼠体内药动学行为及对小鼠镇痛作用研究

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张玮 ¹,² , 杨华娇 ³, , 刘洪伟 ⁴ , 邱喜龙 ⁵ , 尚海花 ⁶,³,

中草药 | 药理与临床 2026,57(16): 6423-6431

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中草药 |药理与临床 2026 , 57 (16) : 6423 -6431

延胡索乙素不同给药方式在神经病理痛模型大鼠体内药动学行为及对小鼠镇痛作用研究

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张玮¹,², 杨华娇³,, 刘洪伟⁴, 邱喜龙⁵, 尚海花⁶,³,

作者信息

^1.天津医科大学肿瘤医院, 恶性肿瘤国家临床医学研究中心, 天津 300060

^2.天津市恶性肿瘤临床医学研究中心, 天津市肿瘤防治重点实验室, 天津 300060

^3.天津天诚新药评价有限公司, 天津 300301

^4.天津中医药大学第一附属医院药学部, 天津 300381

^5.天津中医药大学中药学院, 天津 301617

^6.中国医学科学院放射医学研究所, 天津 300192

^7.天津天诚新药评价有限公司, 天津 300301

通讯作者:

邱喜龙

作者简介:

张玮: 张玮(1986—),药师,本科,从事医院临床药学方向的研究。E-mail:zwgigi8658@126.com

Pharmacokinetic behavior of tetrahydropalmatine via different administration routes in rat model of neuropathic pain and its analgesic effect in mice

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出版时间: 2026-08-28 doi: 10.7501/j.issn.0253-2670.2026.16.017

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目的研究ig与ip 2种给药途径对延胡索乙素（tetrahydropalmatine，THP）在神经病理痛模型大鼠体内药动学行为及组织分布的影响，以小鼠热板法为镇痛药效模型，考察2种给药途径对急性热刺激痛的抑制作用。方法建立快速、灵敏的高效液相色谱-质谱联用（LC-MS/MS）方法，应用于神经病理痛模型大鼠血浆和组织（包括心、肝、脑、肺、肾）中THP浓度的测定，采用WinNonlin 7.0软件非房室模型拟合药动学参数，考察不同时间点THP在大鼠各组织中的分布情况。以温热刺激致舔足潜伏期为评价指标，探究THP经ig和ip 2种给药途径对小鼠的镇痛效果。结果建立了定量测定THP的LC-MS/MS方法，方法学验证结果表明，其在0.5～1 250.0 ng/mL线性关系良好（r＝0.999 3），精密度、准确度及基质效应均符合生物分析要求。药动学结果显示，与ig给药相比，ip给药吸收更快、生物利用度更高。低剂量组ip给药的达峰时间（tmax）为（0.21±0.08）h，与ig给药tmax（0.25±0.00）h相当，但其血药浓度-时间曲线下面积（AUC₀～t）在4 mg/kg剂量下显著高于ig给药。组织分布上，THP在大鼠的主要组织中广泛分布，ip给药组在肝、肾等组织及血浆中多时间点浓度高于ig给药组，其中肝、肾为药物主要富集器官，脑组织亦有较高暴露。药效学结果显示，ig和ip给药均能显著延长温热刺激致小鼠舔足反应的潜伏期，但ip给药组的镇痛作用更优。结论相较于ig给药，ip给药具有吸收更快、生物利用度更高、组织分布更迅速的优势。ig和ip 2种给药途径均有显著的镇痛作用，且以ip给药的镇痛作用最好，验证了药效学与药动学的一致性。

关键词

延胡索乙素 / ip给药 / ig给药 / 药动学行为 / 组织分布 / 镇痛作用

Abstract

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Objective To investigate the effects of ig administration and ip injection on the pharmacokinetic behavior and tissue distribution of tetrahydropalmatine (THP) in neuropathic pain model rats, and to evaluate the analgesic effects of the two administration routes against acute thermal pain in mice using the hot-plate test. Methods A rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for determining THP concentrations in the plasma and tissues (including heart, liver, brain, lung, kidney) of neuropathic pain model rats. The pharmacokinetic parameters were fitted using the non-compartmental model with WinNonlin 7.0 software, and the distribution of THP in various rat tissues at different time points was investigated. Furthermore, the analgesic effects of THP via ig and ip routes in mice were explored, using the licking latency induced by warm thermal stimulation as the evaluation index. Results A quantitative method for determining THP was successfully established. The methodological validation results showed a good linear relationship (r = 0.999 3) between 0.5—1 250.0 ng/mL, the precision, accuracy and matrix effects all met the requirements of biological analysis. Pharmacokinetic results showed that compared with ig administration, ip administration led to faster absorption and higher bioavailability. The time to peak concentration (t_max) for the low-dose ip administration group (0.21 ±0.08) h was comparable to that of ig administration group (0.25 ±0.00) h, but its area under the plasma concentration-time curve (AUC₀_—t) was significantly higher than that of ig administration group at 4 mg/kg dose. Regarding tissue distribution, THP was widely distributed in major rat tissues. At multiple time points, concentrations in the liver, kidney and other tissues, as well as plasma, were higher in ip administration group than in ig administration group. The liver and kidney were identified as the primary drug accumulation organs, and the brain tissue also showed relatively high exposure. Pharmacodynamics results indicated that both ig and ip administration significantly prolonged the licking latency in mice induced by warm thermal stimulation, with the ip administration group showing the best analgesic effect. Conclusion Compared to ig administration, ip administration offers advantages including faster absorption, higher bioavailability and more rapid tissue distribution. Both ig and ip administration routes exhibit significant analgesic effects, with ip administration showing the best efficacy. This verifies the consistency between pharmacodynamics and pharmacokinetics.

Key words

tetrahydropalmatine / ip administration / ig administration / pharmacokinetic behavior / tissue distribution / analgesic effect

引用本文

张玮, 杨华娇, 刘洪伟, 邱喜龙, 尚海花. 延胡索乙素不同给药方式在神经病理痛模型大鼠体内药动学行为及对小鼠镇痛作用研究. 中草药, 2026 , 57 (16) : 6423 -6431 . DOI: 10.7501/j.issn.0253-2670.2026.16.017

ZHANG Wei, YANG Huajiao, LIU Hongwei, QIU Xilong, SHANG Haihua. Pharmacokinetic behavior of tetrahydropalmatine via different administration routes in rat model of neuropathic pain and its analgesic effect in mice[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (16) : 6423 -6431 . DOI: 10.7501/j.issn.0253-2670.2026.16.017

基金

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天津市教育委员会科研计划项目（自然科学类）

参考文献

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参考文献引证文献

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Stanghellini V, Chan F K L, Hasler W L, et al. Gastroduodenal disorders [J]. Gastroenterology, 2016, 150(6):1380-1392.
Black C J, Drossman D A, Talley N J, et al. Functional gastrointestinal disorders: Advances in understanding and management [J]. Lancet, 2020, 396(10263): 1664-1674.
程井, 孙爱玲, 孙凤娟, 等. UPLC-MS/MS法测定不同产地延胡索中原阿片碱、盐酸巴马汀、脱氢紫堇碱、延胡索乙素和延胡索甲素[J]. 现代药物与临床, 2022, 37(6): 1239-1243.
Wauters L, Dickman R, Drug V, et al. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia [J]. United European Gastroenterol J, 2021, 9(3): 307-331.
Peng X N, Tang F, Yang Y, et al. Bidirectional effects and mechanisms of traditional Chinese medicine [J]. J Ethnopharmacol, 2022, 298: 115578.
Su Y, Tao L, Zhang X L, et al. Non-targeted characteristic filter analysis combined with in silico prediction strategies to identify the chemical components and in vivo metabolites of Dalitong Granules by UPLC-Q-TOF/MS/ MS [J]. J Pharm Biomed Anal, 2023, 222: 115086.
江维宁, 吴纯启, 陈瑛, 等. 延胡索甲素与左旋延胡索乙素抗吗啡躯体依赖和精神依赖的作用研究[J]. 药物评价研究, 2016, 39(2):187-192.
He W, Liu M Y, Li Y M, et al. Flavonoids from Citrus aurantium ameliorate TNBS-induced ulcerative colitis through protecting colonic mucus layer integrity [J]. Eur J Pharmacol, 2019, 857: 172456.
Zheng H, Chen Y L, Zhang J Z, et al. Evaluation of protective effects of costunolide and dehydrocostuslactone on ethanol-induced gastric ulcer in mice based on multi-pathway regulation [J]. Chem Biol Interact, 2016, 250: 68-77.
高淑红, 谢跃生, 肖学凤, 等. 杠柳毒苷在大鼠体内的组织分布[J]. 现代药物与临床, 2011, 26(2): 116-118.
于定荣, 翁小刚, 王本晓, 等. 延胡索、白芷炮制配伍对元胡止痛方中延胡索乙素、欧前胡素含量以及镇痛作用的影响[J]. 中草药, 2021, 52(8): 2306-2312.
李梦雅, 丁玉, 辛娟, 等. 马来酰亚胺修饰延胡索乙素纳米粒的制备、药动学及其对急性肝损伤的保护作用研究[J]. 药物评价研究, 2025, 48(9): 2565-2578.
林力, 刘建勋, 张颖, 等. LC-MS/MS法测定大鼠口服延胡索提取物后延胡索乙素和脱氢紫堇碱的药代动力学[J]. 药学学报, 2008, 43(11): 1123-1127.
Xing J F, You H S, Dong Y L, et al. Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces [J]. Acta Pharmacol Sin, 2011, 32(5): 655-663.
Zhao Y, Hellum B H, Liang A H, et al. Inhibitory mechanisms of human CYPs by three alkaloids isolated from traditional Chinese herbs [J]. Phytother Res, 2015, 29(6): 825-834.
陈刚, 马莉, 韩锋, 等. HPLC法测定肾康颗粒中延胡索乙素[J]. 现代药物与临床, 2011, 26(5): 406-408.
Ho Kim S, Mo Chung J. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat [J]. PAIN, 1992, 50(3): 355-363.
代丽娜, 李曦, 杨玉兰, 等. 延胡索乙素对神经病理痛大鼠镇痛作用及机制研究[J]. 中国处方药, 2023, 21(6): 42-45.
Davies B, Morris T. Physiological parameters in laboratory animals and humans [J]. Pharm Res, 1993, 10(7): 1093-1095.
Ward K W, Azzarano L M, Bondinell W E, et al. Preclinical pharmacokinetics and interspecies scaling of a novel vitronectin receptor antagonist 1[J]. Drug Metab Dispos, 1999, 27(11): 1232-1241.

2026年第57卷第16期

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doi: 10.7501/j.issn.0253-2670.2026.16.017

接收时间：2025-12-18
首发时间：2026-10-22
出版时间：2026-08-28

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收稿日期：2025-12-18

基金

天津市教育委员会科研计划项目（自然科学类）

作者信息

^1.天津医科大学肿瘤医院, 恶性肿瘤国家临床医学研究中心, 天津 300060

^2.天津市恶性肿瘤临床医学研究中心, 天津市肿瘤防治重点实验室, 天津 300060

^3.天津天诚新药评价有限公司, 天津 300301

^4.天津中医药大学第一附属医院药学部, 天津 300381

^5.天津中医药大学中药学院, 天津 301617

^6.中国医学科学院放射医学研究所, 天津 300192

^7.天津天诚新药评价有限公司, 天津 300301

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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