不同剂型普罗布考对大鼠肠系膜淋巴转运及药代动力学的影响

doi:10.12300/j.issn.1674-5817.2022.026

实验动物与比较医学 ›› 2022, Vol. 42 ›› Issue (4): 275-283.DOI: 10.12300/j.issn.1674-5817.2022.026

• 动物实验技术与方法专题 • 上一篇下一篇

不同剂型普罗布考对大鼠肠系膜淋巴转运及药代动力学的影响

张笑瑞¹(), 曹静², 吴倩倩¹, 刘季俊¹, 陈国元¹, 吴宝金¹()()

^1.中国科学院分子细胞科学卓越创新中心动物实验技术平台, 上海 200031
^2.上海中医药大学实验动物中心, 上海 200031

收稿日期:2022-03-04 修回日期:2022-07-19 出版日期:2022-08-25 发布日期:2022-09-01
通讯作者: 吴宝金（1969—），男，博士，研究员，研究方向：小鼠遗传学和人类疾病动物模型。E-mail：baojin.wu@sibcb.ac.cn。ORCID： 0000-0002-9768-8862
作者简介:张笑瑞（1987—），男，工程师，研究方向：人类疾病动物模型与新药临床前评价。E-mail：xiaorui.zhang@sibcb.ac.cn
基金资助:
中国科学院战略生物资源计划实验动物平台项目-2022年度实验动物模型研发子课题(KFJ-BRP-005)

Effects of Probucol Formulations on Mesenteric Lymphatic Trans-port Efficiency and Pharmacokinetics in Rats

Xiaorui ZHANG¹(), Jing CAO², Qianqian WU¹, Jijun LIU¹, Guoyuan CHEN¹, Baojin WU¹()()

^1.Animal Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China
^2.Experiment Animal Center, Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China

Received:2022-03-04 Revised:2022-07-19 Published:2022-08-25 Online:2022-09-01
Contact: WU Baojin (ORCID: 0000-0002-9768-8862), E-mail: baojin.wu@sibcb.ac.cn

摘要/Abstract

摘要：

目的通过一种新型的肠系膜淋巴管-颈静脉辅助回流模型，比较普罗布考橄榄油制剂与普罗布考混悬液制剂对大鼠肠系膜淋巴转运及药代动力学的影响。方法 12只SD大鼠随机分为4组，即混悬液制剂-颈静脉单插管组（H-JD组）、混悬液制剂-颈静脉和肠淋巴管双插管组（H-JCS组）、橄榄油制剂-颈静脉单插管组（G-JD组）、橄榄油制剂-颈静脉和肠淋巴管双插管组（G-JCS组）。用液相色谱和串联质谱联用（LC-MS/MS）法测定各组大鼠在不同时间全血和淋巴液中普罗布考的浓度，绘制药-时曲线，计算药代动力学参数、相对生物利用度（F_rel）和淋巴液剂量百分比。结果各组的药-时曲线符合非房室模型。前述各组到达峰值时间（T_max）分别为（11±12）h、（5±2）h、（13±9）h和（19±9）h；到达峰值浓度（C_max）分别为（148±60）ng/mL、（207±137）ng/mL、（453±204）ng/mL和（309±177）ng/mL；药-时曲线下面积（AUC_last）分别为（3 210±885）h·ng·mL^-1、（3 677±2 014）h·ng·mL^-1、（12 360±6 629）h·ng·mL^-1和（8 080±3 064）h·ng·mL^-1。H-JCS组和G-JCS组的淋巴液剂量百分比分别为（1.29±0.50）%和（2.59±0.43）%。与H-JD组相比，G-JD组中普罗布考的F_rel为（409±269）%；与H-JCS组相比，G-JCS组中普罗布考的F_rel为（309±256）%。与H-JD组和H-JCS组相比，G-JD组和G-JCS组大鼠全血的C_max、T_max、AUC_last和淋巴液剂量百分比显著升高（P＜0.05）；其中G-JD组全血的AUC_last显著高于G-JCS组（P＜0.05），而H-JD组和H-JCS组差异无统计学意义（P > 0.05）。结论使用橄榄油制剂可以提高普罗布考通过肠系膜淋巴液的转运吸收率和生物利用度。

关键词: 普罗布考, 肠系膜淋巴液, 药代动力学, 转运, SD大鼠

Abstract:

Objective To compare the effects of probucol olive oil and suspension formulations on the pharmacokinetics and mesenteric lymphatic transport in rats using an innovative mesenteric-jugular lymphatic duct assisted reflux model. Methods Twelve Sprague-Dawley (SD) rats were randomly divided into four groups: suspension preparation-jugular vein single cannulation group (H-JD group), suspension preparation-jugular vein and intestinal lymphatic double cannulation group (H-JCS group), olive oil preparation-jugular vein single cannulation group (G-JD group), olive oil preparation-jugular vein and intestinal lymphatic double cannulation group (G-JCS group). The concentrations of probucol in whole blood and lymph fluid of rats at different times were determined by liquid chromatography and tandem mass spectrometry (LC-MS/MS), and drug-time curves were drawn. The pharmacokinetic parameters, relativebioavailability (F_rel) and percentage dose in lymph fluid were calculated. Results The drug-time curve of each group conformed to the non-compartmental model. The peak times (T_max) of the H-JD group, H-JCS group, G-JD group, and G-JCS group were (11±12), (5±2), (13±9), and (19±9) h, respectively; the peak concentrations (C_max) were (148±60), (207±137), (453±204), and (309±177) ng/mL, respectively; the areas under the curve (AUC_last) were (3 210±885), (3 677±2 014), (12 360±6 629), and (8 080±3 064) h·ng·mL^-1, respectively. The percentages of lymphatic fluid dose in the H-JCS and G-JCS groups were (1.29±0.50)% and (2.59±0.43)%. Compared with the H-JD group, the F_rel of probucol in the G-JD group was (409±269)%; compared with the H-JCS group, the F_rel of probucol in the G-JCS group was (309±256)%. Compared with the H-JD and H-JCS groups, the whole blood values of C_max, T_max, AUC_last and percentage of lymphatic fluid probucol concentrations of the G-JD and the G-JCS groups were significantly increased (P＜0.05). The AUC_last of whole blood in the G-JD group was significantly higher than that in the G-JCS group (P＜0.05), but there was no significant difference between the H-JD and H-JCS groups (P > 0.05). Conclusion Olive oil formulation can improve the ratio of probucol transport through mesenteric lymph as well as its bioavailability.

Key words: Probucol, Mesenteric lymph fluid, Pharmacokinetics, Transport, Sprague-Dawley rats

中图分类号:

Q95-33

张笑瑞, 曹静, 吴倩倩, 刘季俊, 陈国元, 吴宝金. 不同剂型普罗布考对大鼠肠系膜淋巴转运及药代动力学的影响[J]. 实验动物与比较医学, 2022, 42(4): 275-283.

Xiaorui ZHANG, Jing CAO, Qianqian WU, Jijun LIU, Guoyuan CHEN, Baojin WU. Effects of Probucol Formulations on Mesenteric Lymphatic Trans-port Efficiency and Pharmacokinetics in Rats[J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 275-283.

图/表 7

图1 普罗布考色谱图注：A示空白全血的色谱图，B示空白淋巴液的色谱图，C示全血中添加普罗布考（1 ng/mL）的色谱图，D示淋巴液中添加普罗布考（1 ng/mL）的色谱图。

Figure 1 Chromatogram of blood and lymph with and without probucolNote: (A) Blank whole blood; (B) Blank lymph fluid; (C) Probucol (1 ng/mL) added to whole blood; (D) Probucol (1 ng/mL) added to lymph fluid.

图2 普罗布考的标准曲线图注：A示普罗布考在全血中的标准曲线图，B示普罗布考在淋巴液中的标准曲线图。

Figure 2 Standard curves of probucol in blood and lymphNote：(A) Probucol in whole blood; (B) Probucol in lymph fluid.

表1 各组大鼠的血药浓度 (± s，n=3)

Table 1 Drug concentrations in the blood of rats in each group

采血时间 Blood collection time/h	普罗布考Probucol ρ/(ng·mL^-1)
采血时间 Blood collection time/h	H-JD组 H-JD group	H-JCS组 H-JCS group	G-JD组 G-JD group	G-JCS组 G-JCS group
0	-	-	-	-
0.25	-	-	-	-
0.5	5	-	-	-
1	34±7	28±32	13±5	-
2	62±48	38±32	76±30	19±23
4	126±91	188±167	143±26	82±119
8	104±87	100±36	379±138	128±184
24	67±30	69±49	289±296	252±189
48	12±5	22±15	85±23	48±13
72	5±1	11±10	15±5	18±1

图3 各组大鼠的药物浓度-时间曲线（A）和淋巴液剂量百分比曲线（B）注：H-JD组指混悬液制剂-颈静脉单插管组；H-JCS组指混悬液制剂-颈静脉和肠淋巴管双插管组；G-JD组指橄榄油制剂-颈静脉单插管组；G-JCS组指橄榄油制剂-颈静脉和肠淋巴管双插管组。

Figure 3 Drug concentration-time curve (A) and dose percentage curve of lymphatic fluid (B) in all groups of ratsNote: H-JD, suspension preparation-jugular vein single cannulation group; H-JCS, suspension preparation-jugular vein and intestinal lymphatic double cannulation group; G-JD, olive oil preparation-jugular vein single cannulation group; G-JCS, olive oil preparation-jugular vein and intestinal lymphatic double cannulation group.

表2 各组大鼠的全血药动学参数 (± s，n=3)

Table 2 Pharmacokinetic parameters of the whole blood of rats in each group

参数 Parameters	H-JD组 H-JD group	H-JCS组 H-JCS group	G-JD组 G-JD group	G-JCS组 G-JCS group
峰值时间T_max/h	11±12	5±2	13±9	19±9
峰值浓度C_max/(ng·mL^-1)	148±60	207±137	453±204	309±177
半衰期T_1/2/h	12±1	17±3	13±3	19±11
药-时曲线下面积AUC_last/(h·ng·mL^-1)	3 210±885	3 677±2 014	12 360±6 629	8 080±3 064
药-时曲线下面积AUC_INF/(h·ng·mL^-1)	3 293±899	3 970±2 295	12 623±6 650	8 947±2 218

表3 各组大鼠的相对生物利用度（Frel） (n=3)

Table 3 Relative bioavailability (Frel) of rats in each group

动物 Rat	药-时曲线下面积AUC_last/(h·ng·mL^-1)		F_rel/%	药-时曲线下面积AUC_last/(h·ng·mL^-1)		F_rel/%
动物 Rat	H-JD组 H-JD group	G-JD组 G-JD group	F_rel/%	H-JCS组 H-JCS group	G-JCS组 G-JCS group	F_rel/%
第1只No.1	2 750	19 800	720	3 360	8 680	258
第2只No.2	4 230	10 200	241	1 840	10 800	587
第3只No.3	2 650	7 080	267	5 830	4 760	82
平均数 $x ¯$ ±s	3 210±885	12 360±6 629	409±269	3 677±2 014	8 080±3 064	309±256

表3 各组大鼠的相对生物利用度（Frel） (n=3)

Table 3 Relative bioavailability (Frel) of rats in each group

动物 Rat	药-时曲线下面积AUC_last/(h·ng·mL^-1)		F_rel/%	药-时曲线下面积AUC_last/(h·ng·mL^-1)		F_rel/%
动物 Rat	H-JD组 H-JD group	G-JD组 G-JD group	F_rel/%	H-JCS组 H-JCS group	G-JCS组 G-JCS group	F_rel/%
第1只No.1	2 750	19 800	720	3 360	8 680	258
第2只No.2	4 230	10 200	241	1 840	10 800	587
第3只No.3	2 650	7 080	267	5 830	4 760	82
平均数 $x ¯$ ±s	3 210±885	12 360±6 629	409±269	3 677±2 014	8 080±3 064	309±256

表4 各组大鼠的淋巴液剂量百分比参数 (± s，n=3)

Table 4 Dose percentage parameters of lymphatic fluid of rats in each group

参数 Parameters	采液时间/h Liquid collection time/h	H-JCS组 H-JCS group	G-JCS组 G-JCS group
质量浓度ρ/（ng·mL^-1）	0~4	2 880±2 120	2 862±968
	4~8	5 682±4 935	4 019±4 019
	8~24	417±189	1 345±1 695
体积V/mL	0~4	6.8±0.5	11.0±2.0
	4~8	7.2±0.6	19.2±1.4
	8~24	20.8±2.4	30.4±3.0
剂量百分比Dose percentage/%	0~4	0.37±0.26	0.60±0.25
	0~8	1.13±0.87	1.85±0.88
	0~24	1.29±0.50	2.59±0.43

参考文献 23

1	HIRATA K I. New evidence of probucol on cardiovascular events[J]. J Atheroscler Thromb, 2021, 28(2):97-99. DOI:10.5551/jat.ED155 .
2	YAMASHITA S, MASUDA D, OHAMA T, et al. Rationale and design of the PROSPECTIVE trial: probucol trial for secondary prevention of atherosclerotic events in patients with prior coronary heart disease[J]. J Atheroscler Thromb, 2016, 23(6):746-756. DOI:10.5551/jat.32813 .
3	LIU J C, LI M H, LU H, et al. Effects of probucol on restenosis after percutaneous coronary intervention: a systematic review and meta-analysis[J]. PLoS One, 2015, 10(4): e0124021. DOI:10.1371/journal.pone.0124021 .
4	HIGASHI K, MORI A, SAKAMOTO K, et al. Probucol slows the progression of cataracts in streptozotocin-induced hyperglycemic rats[J]. Pharmacology, 2019, 103(3-4):212-219. DOI:10.1159/000496055 .
5	JUNG Y S, PARK J H, KIM H, et al. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice[J]. Acta Pharmacol Sin, 2016, 37(8):1031-1044. DOI:10.1038/aps.2016.51 .
6	HAN L M, YANG Q S, SHEN T, et al. Lymphatic transport of orally administered probucol-loaded mPEG-DSPE micelles[J]. Drug Deliv, 2016, 23(6):1955-1961. DOI:10.3109/10717544.2015.1028600 .
7	QIAN Y W, CHEN G G, WANG J, et al. Preparation and evaluation of probucol-phospholipid complex with enhanced bioavailability and No food effect[J]. AAPS Pharmscitech, 2018, 19(8):3599-3608. DOI:10.1208/s12249-018-1157-2 .
8	GERSHKOVICH P, HOFFMAN A. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability[J]. Eur J Pharm Sci, 2005, 26(5):394-404. DOI:10.1016/j.ejps.2005.07.011 .
9	YÁÑEZ J A, WANG S W J, KNEMEYER I W, et al. Intestinal lymphatic transport for drug delivery[J]. Adv Drug Deliv Rev, 2011, 63(10-11):923-942. DOI:10.1016/j.addr.2011.05.019 .
10	BEG S, ALAM M N, AHMAD F J, et al. Chylomicron mimicking nanocolloidal carriers of rosuvastatin calcium for lymphatic drug targeting and management of hyperlipidemia[J]. Colloids Surf B Biointerfaces, 2019, 177:541-549. DOI:10.1016/j.colsurfb.2019.02.039 .
11	HOKKANEN K, TIRRONEN A, YLÄ-HERTTUALA S. Intestinal lymphatic vessels and their role in chylomicron absorption and lipid homeostasis[J]. Curr Opin Lipidol, 2019, 30(5):370-376. DOI:10.1097/MOL.0000000000000626 .
12	KIM H, SEONG I, RO J, et al. Enhanced association of probucol with chylomicron by pharmaceutical excipients: an in vitro study[J]. Drug Dev Ind Pharm, 2015, 41(7):1073-1079. DOI:10.3109/03639045.2014.927479 .
13	张笑瑞, 曹静, 吴倩倩, 等. 大鼠肠系膜淋巴液持续引流新方法的初步建立[J]. 实验动物与比较医学, 2022, 42(4):267-274. DOI:10.12300/j.issn.1674-5817.2022.024 .
	ZHANG X R, CAO J, WU Q Q, et al. A preliminary method for continuous drainage of mesenteric lymph fluid in rat[J]. Laboratory Animal and Comparative Medicine, 2022, 42(4):267-274. DOI:10.12300/j.issn.1674-5817.2022.024 .
14	ALEXANDER J S, GANTA V C, JORDAN P A, et al. Gastrointestinal lymphatics in health and disease[J]. Pathophysiology, 2010, 17(4):315-335. DOI:10.1016/j.pathophys. 2009.09.003 .
15	HYEONGMIN K, YEONGSEOK K, JAEHWI L E. Liposomal formulations for enhanced lymphatic drug delivery[J]. Asian J Pharm Sci, 2013(2):96-103.
16	MARWAHA R K, DABAS A. Bioavailability of nanoemulsion formulations vs conventional fat soluble preparations of cholecalciferol (D3) - An overview[J]. J Clin Orthop Trauma, 2019, 10(6):1094-1096. DOI:10.1016/j.jcot.2019.07.014 .
17	ZHANG Y M, ZHANG S K, CUI N Q. Intravenous infusion of mesenteric lymph from severe intraperitoneal infection rats causes lung injury in healthy rats[J]. World J Gastroenterol, 2014, 20(16):4771-4777. DOI:10.3748/wjg.v20.i16.4771 .
18	CHAMPAGNE D, PEARSON D, DEA D, et al. The cholesterol-lowering drug Probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer's disease[J]. Neuroscience, 2003, 121(1):99-110. DOI:10.1016/S0306-4522(03)00361-0 .
19	BROCKS D R, DAVIES N M. Lymphatic drug absorption via the enterocytes: pharmacokinetic simulation, modeling, and considerations for optimal drug development[J]. J Pharm Pharm Sci, 2018, 21(1s):254s-270s. DOI:10.18433/jpps30217 .
20	LI J, YANG Y, ZHAO M H, et al. Improved oral bioavailability of probucol by dry media-milling[J]. Mater Sci Eng C, 2017, 78:780-786. DOI:10.1016/j.msec.2017.04.141 .
21	SCHÖNFELD P, WOJTCZAK L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective[J]. J Lipid Res, 2016, 57(6):943-954. DOI:10.1194/jlr.R067629 .
22	TANOUS D, BRÄSEN J H, CHOY K, et al. Probucol inhibits in-stent thrombosis and neointimal hyperplasia by promoting re-endothelialization[J]. Atherosclerosis, 2006, 189(2):342-349. DOI:10.1016/j.atherosclerosis.2006.01.025 .
23	KOSTIK V, MEMETI S, BAUER B. Fatty acid composition of edible oils and fats[J]. J Hyg Eng Des, 2013, 4: 112-116.

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不同剂型普罗布考对大鼠肠系膜淋巴转运及药代动力学的影响

Effects of Probucol Formulations on Mesenteric Lymphatic Trans-port Efficiency and Pharmacokinetics in Rats

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