硫酸软骨素及其寡糖在大鼠体内的药代动力学和口服绝对生物利用度研究  

Pharmacokinetics and Oral Absolute Bioavailability of Chondroitin Sulfate and Its Oligosaccharides in Rats

作　　者：王杰 戴启杰 杨桃 孟俊东 孙建国[2] WANG Jie;DAI Qijie;YANG Tao;MENG Jundong;SUN Jianguo(Nanjing Hanxin Pharmaceutical Technology Co.,Ltd,Nanjing 210046,China;China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]南京汉欣医药科技有限公司,江苏南京210046 [2]中国药科大学多靶标天然药物全国重点实验室,江苏南京211198

出　　处：《药物生物技术》2025年第1期33-38,共6页Pharmaceutical Biotechnology

摘　　要：考察不同给药方式下,硫酸软骨素(chondroitin sulfate,CS)和硫酸软骨素寡糖(chondroitin sulfate oligosaccharide,CSO)在sprague dawley(SD)大鼠体内的药代动力学参数差异,及各自绝对生物利用度。以SD大鼠为实验对象,设置CS 30 mg/kg静脉注射给药组、CS 1000 mg/kg灌胃给药组、CSO 2 mg/kg静脉给药组和CSO 21 mg/kg灌胃给药组。单次给药,分别在给药前及给药后对大鼠进行采血,分离血浆。建立LC-MS/MS分析方法,并检测收集到的血浆样本,计算分析并比较CS与CSO的血浆药代动力学参数差异,并尝试利用Winnonlin药代动力学软件拟合CSO静脉注射分布情况。检测选择流动相A:200 mmol/L乙酸铵(pH 9.0)∶水=10∶90,流动相B:200 mmol/L乙酸铵(pH 9.0)∶乙腈=10∶90作为流动相,质谱中相应信号稳定,检测物在5.22~3130 ng/mL范围内线性关系良好,重复性好,准确性RSD为5.7%,回收率均值100.6%。此检测方法下,CS与CSO静脉注射组,迅速达峰,达峰浓度C_(max)分别为(1.10±0.06)×10^(5)ng/mL、(1783.00±373.50)ng/mL,并迅速消除。CS灌胃给药组达峰时间T_(max)为(400.00±195.96)min,达峰浓度C_(max)为(183.00±99.00)ng/mL,曲线下面积AUC_(last)为(2.70±0.99)×10^(4)(min·ng)/mL,口服绝对生物利用度F%为(0.02±0.01)%。CSO灌胃给药组达峰时间T_(max)为(49.17±67.34)min,达峰浓度C_(max)为(129.60±123.10)ng/mL,曲线下面积AUC_(last)为(1.60±2.20)×10^(4)(min·ng)/mL,口服绝对生物利用度F%为(3.16±4.25)%。CSO静注组拟合二室模型中,C_(max)为(136625.53±13917.58)ng/mL,AUC为(6.64±5.62)×10~6(min·ng)/mL。本实验建立的检测方法,线性、重复性良好,准确度高,快速、高效,适用于CS及CSO在大鼠血浆中的药代动力学参数测定,CSO静脉注射在大鼠体内可能的最佳房室模型为二室。与CS相比,CSO具有更高的生物利用度,更高的吸收率和更快的吸收速率,CSO的独特药动学优势有利于其在骨关节炎治疗适应症中的开发。The pharmacokinetic parameters and absolute bioavailability of chondroitin sulfate(CS)and chondroitin sulfate oligosaccharide(CSO)in sprague dawley(SD)rats were investigated under different administration modes.SD rats were divided into four groups:CS 30 mg/kg intravenous group,CS 1000 mg/kg intragastric administration group,CSO 2 mg/kg intravenous group and CSO 21 mg/kg intragastric administration group.After single administration,bloods were collected from rats before and after administration,and plasma was separated for assay.The LC-MS/MS analysis method was established,and the plasma samples were detected.The differences of plasma pharmacokinetic parameters between CS and CSO were analyzed.Together,Winnonlin pharmacokinetic software was used to fit the distribution parameters after CSO intravenous injection.The mobile phase were,A:200 mm ammonium acetate(pH 9.0)∶water=10∶90,and mobile phase B:200 mm ammonium acetate(pH 9.0)∶acetonitrile=10∶90.The corresponding signals in mass spectrometry were stable,and the linear relationship between the detected substances was good in the range of 5.22~3130 ng/mL.The repeatability was good,the RSD is 5.7%and the average recovery rate was 100.6%.Under this detection method,the CS and CSO intravenous groups reached the peak rapidly,and the peak concentration(C_(_(max)))was(1.10±0.06)×10^(5)ng/mL and(1783.00±373.50)ng/mL,respectively,and then quickly eliminated.The T_(_(max))of CS intragastric administration group was(400.00±195.96)min,the C_(_(max))was(183.00±99.00)ng/mL,the AUC_(_(last))was(2.70±0.99)×10^(4)(min·ng)/mL,the oral absolute bioavailability(F%)was(0.02±0.01)%.The T_(_(max))of the CSO intragastric administration group was(49.17±67.34)min,the C_(_(max))was(129.60±123.10)ng/mL,and the AUC_(_(last))were(1.60±2.20)×10^(4)(min·ng)/mL,the oral absolute bioavailability(F%)was(3.16±4.25)%.The fitted two-compartment model of CSO intravenous injection group showed that C_(_(max))was(136625.53±13917.58)ng/mL and AUC was(6.64±5.62)×10~6(min·ng)/mL.

关 键 词：硫酸软骨素寡糖 LC-MS/MS 药代动力学 生物利用度 骨关节炎 房室模型 

分 类 号：R914[医药卫生—药物化学]