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（t_max）为（0.21±0.08）h，与ig给药t_max（0.25±0.00）h相当，但其血药浓度-时间曲线下面积（AUC_0～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。

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 (AUC_0—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.

R285.61

天津市教育委员会科研计划项目（自然科学类）（2017KJ130）