克班宁贴剂在大鼠体内的药动学与药效学评价

崔利利; 李婧瑜; 徐鹤; 杨子贤; 马云淑

doi:10.14148/j.issn.1672-0482.2022.1062

克班宁贴剂在大鼠体内的药动学与药效学评价

doi: 10.14148/j.issn.1672-0482.2022.1062

崔利利^{1, 2,},
李婧瑜^{1, 3},
徐鹤¹,
杨子贤¹,
马云淑^{1, 4, 5, ,}

1.
云南中医药大学中药学院, 云南昆明 650500
2.
南京中医药大学药学院, 江苏南京 210023
3.
云南省疾病预防控制中心, 云南昆明 650000
4.
云南省傣彝学重点实验室, 云南昆明 650500
5.
云南省南药可持续利用重点实验室, 云南昆明 650500

基金项目:

国家自然科学基金面上项目 82060723

国家自然科学基金面上项目 82174065

详细信息

作者简介:
崔利利, 女, 博士研究生, E-mail: cuilili1015@163.com

马云淑，教授，博士生导师。云南省特殊津贴专家，云南省高校外用给药系统重点实验室负责人; 省特色专业、省一流课程、省研究生导师团队与优质课程负责人; 中国中医药促进会外治分会副会长。主持国家自然科学基金项目6项，省科技厅重点项目2项与重大专项子项目2项，横向课题等20余项。以第一和通讯作者发表论文140余篇，获云南省科技进步三等奖与中国中西医结合学会科技奖等

通讯作者:
马云淑, 女, 教授, 主要从事中药新型给药系统研究，E-mail: yunshuma2@126.com

中图分类号: R285.5
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- 被引次数: 0
出版历程
- 收稿日期: 2022-04-07
- 网络出版日期: 2022-11-19
- 发布日期: 2022-11-10

Pharmacokinetic and Pharmacodynamic Evaluation of Crebanine Patch in Rats

CUI Li-li^{1, 2
,},
LI Jing-yu^{1, 3},
XU He¹,
YANG Zi-xian¹,
MA Yun-shu^{1, 4, 5
, ,}

1.
College of Chinese Material Medica, Yunnan University of Chinese Medicine, Kunming 650500, China
2.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
3.
Yunnan Center for Disease Control and Prevention, Kunming 650000, China
4.
Yunnan Key Laboratory of Dai and Yi Medicine, Kunming 650500, China
5.
Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Kunming 650500, China

摘要

摘要: 目的比较克班宁经皮和灌胃2种给药途径在大鼠体内的药动学差异性，评价克班宁贴剂经皮给药抗大鼠心律失常的效果, 以及克班宁对钙离子通道的作用机制。方法采用HPLC法测定大鼠血浆中克班宁的浓度; 采用氯化钡(BaCl₂)致大鼠心律失常的模型观察克班宁经皮给药的抗心律失常效果, 采用Whole Cell记录检测克班宁对钙通道电流的影响。结果克班宁贴剂经皮给药(400 mg·kg^-1)的主要药动学参数为: AUC_0-∞=(204.500±170.496)mg·h·L^-1; T_max=(10.333±0.745)h; C_max=(1.968±0.147)mg·L^-1(n=6)。克班宁溶液灌胃给药(40 mg·kg^-1)的主要药动学参数为: AUC_0-∞=(26.980±6.672)mg·h·L^-1; T_max=(0.086±0.024)h; C_max=(8.991±2.343)mg·L^-1(n=6)。与阴性组比较, 79、158、316 mg·kg^-1三个剂量克班宁贴剂组大鼠经皮给药后, 恢复窦性心律所需的时间均显著缩短(P < 0.01), 恢复窦性心律的鼠数均明显增多(P < 0.01);给药后≤20 min能够恢复窦性心律的鼠数均明显增多(P < 0.001);恢复窦性心律后维持时间>20 min的鼠数显著增多(P < 0.01)。克班宁对T型钙通道和L型钙通道均有较明显的抑制作用。结论克班宁贴剂给药在大鼠体内消除慢, 具有缓释作用, 可通过抑制钙离子通道发挥对BaCl₂致大鼠心律失常的明显抑制作用, 显著延长作用时间, 达到减毒增效的目的。
- 克班宁 /
- 贴剂 /
- 灌胃 /
- 药动学 /
- 抗心律失常 /
- 钙通道
Abstract: OBJECTIVE To compare the pharmacokinetic differences between the percutaneous and intragastric administration of Crebanine in rats. To evaluate the effect of Crebanine patch on anti-arrhythmia in rats and the mechanism of Crebanine on calcium channel. METHODS The plasma concentration of Crebanine in rats was determined by HPLC. The anti-arrhythmic effect of Crebanine transdermal administration was observed in the model of barium chloride induced arrhythmia in rats, and Whole Cell recording was used to detect the effect of Crebanine on calcium channel current. RESULTS The main pharmacokinetic parameters of Crebanine patch for transdermal administration (400 mg·kg^-1) were as follows: AUC_0-∞=(204.500±170.496)mg·h·L^-1; T_max=(10.333±0.745)h; C_max=(1.968±0.147)mg·L^-1 (n=6). The main pharmacokinetic parameters of Crebanine solution for intragastric administration (40 mg·kg^-1) were as follows: AUC_0-∞=(26.980±6.672)mg·h·L^-1; T_max=(0.086±0.024)h; C_max=(8.991±2.343)mg·L^-1 (n=6). Compared with the negative group, the time required for recovery of sinus rhythm was significantly shortened (P < 0.01), and the number of rats recovering sinus rhythm significantly increased (P < 0.01) after transdermal administration of the patches in 79, 158, 316 mg·kg^-1 groups. The number of rats that could recover sinus rhythm within 20 min after administration increased significantly (P < 0.001). The number of rats that maintained sinus rhythm for more than 20 min after the restoration increased significantly (P < 0.01). Both T-type and L-type calcium channels were inhibited by Crebanine. CONCLUSION The administration of Crebanine patch has slow elimination and sustained release effect, can significantly inhibit barium chloride induced arrhythmia in rats by inhibiting calcium channels, and significantly prolong the action time, so as to achieve the purpose of reducing toxicity and increasing efficiency.
- Crebanine /
- patch /
- intragastric administration /
- pharmacokinetics /
- anti-arrhythmia /
- calcium channels

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图 1 克班宁血浆HPLC谱图

注：A.空白血浆；B.空白血浆+内标+克班宁溶液; C.克班宁贴剂给药；1.维拉帕米; 2.克班宁

Figure 1. HPLC chromatogram of Cre

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图 2 克班宁贴剂给药血药浓度-时间曲线(x±s，n=6)

Figure 2. Drug-time curve of Cre administration by patch (x±s, n=6)

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图 3 克班宁灌胃给药血药浓度-时间曲线(x±s，n=6)

Figure 3. Drug-time curve of Cre administration by gavage (x±s, n=6)

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图 4 30 μmol·L^-1克班宁对L-type、T-type Ca²⁺通道的抑制作用

Figure 4. Inhibitory effect of 30 μmol·L^-1 Cre on L-type and T-type Ca²⁺ channels

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图 5 克班宁对L-type、T-type Ca²⁺通道的剂量效应关系

Figure 5. Dose-response relationship of Cre on L-type and T-type Ca²⁺ channels

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表 1 克班宁经皮、灌胃给药在大鼠体内的房室模型参数

Table 1. Compartment model parameters of transdermal, gavage administration of Cre in rats

参数	t_1/2α/h	AUC_0-∞/(mg·h·L^-1)	MRT_0-∞/h	T_max/h	C_max/(mg·L^-1)
克班宁灌胃组	0.274±0.082	26.980±6.672	-	0.086±0.024	8.991±2.343
克班宁贴剂阴性组	-	117.653±45.403	122.100±74.640	14.000±10.066	1.299±0.647
克班宁贴剂阳性组	-	152.099±80.078	120.762±114.646	9.333±0.943	1.801±0.710
克班宁贴剂实验组	-	204.500±170.496	187.428±243.590	10.333±0.745	1.968±0.147

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表 2 克班宁贴剂经皮与灌胃给药对BaCl₂致大鼠心律失常的影响(x±s，n=10)

Table 2. Effect of transdermal and gavage administration of Cre patch on arrhythmia caused by BaCl₂ (x±s, n=10)

组别	n	剂量/(mg·kg^-1)	平均恢复时间/s	给药后≤10 min恢复窦性心律的鼠数	给药后≤20 min恢复窦性心律的鼠数	恢复窦性心律后维持时间>20 min的鼠数
空白对照组	10	-	-	-	-	-
阴性组	10	-	2 316.8±1 432.9	0	1	3
阳性组	10	30	207.9±139.0^**	10^***	10^***	10^***
克班宁低剂量组	10	79	568.3±316.2^**	6^**	10^***	9^**
克班宁中剂量组	10	158	383.5±247.5^**	8^***	10^***	10^**
克班宁高剂量组	10	316	417.2±196.8^**	8^***	10^***	10^**
注: 与阴性组比较, ^P < 0.01，^*P < 0.001。

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