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不同BCS分类药物的肠道渗透性研究
不同BCS分类药物的肠道渗透性研究
慈小燕1,2,武卫党1,2,李亚卓1,2,谷 元1,2,伊秀林1,2,司端运1,2,曾 勇1,2,刘昌孝1,2

1 天津药物研究院新药评价有限公司,释药技术与药代国家重点实验室,天津 300193;2 天津滨海食品药品监管科学研究中心,天津 300193
Investigating intestinal permeability of different BCS classification drugs
(1 Tianjin Institute of Pharmaceutical Research, State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin 300193, China; 2 Tianjin Binhai Research Center ofFood and Drug Regulatory, Tianjin 300193, China)

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起始页:63

摘要:[摘要] 目的:研究国家食品药品监督管理总局(CFDA)颁发的《生物等效性豁免指导原则》中不同生物药剂学分类系统(BCS)分类工具药的肠道渗透性,建立药物的肠道渗透性评价体系及药物表观渗透系数与其对应渗透性类别的相关性,为药物的BCS分类提供依据。方法:应用Caco-2细胞模型研究高渗透性药物(安替比林、咖啡因、茶碱、卡马西平、普萘洛尔、米诺地尔、美托洛尔、苯妥英钠)、中渗透性药物(二甲双胍、雷尼替丁)、低渗透性药物(甘露醇)、零渗透性药物(荧光黄)、外排机制药物(地高辛、罗丹明123)的肠道渗透性及其时间依赖。结果:电阻值表示本细胞模型致密性良好;罗丹明123和地高辛均呈现良好的外排,加入P-gp抑制剂维拉帕米后均有较明显的抑制,表明本细胞模型具有良好的外排能力。在研究的高渗透性药物中,安替比林的表观渗透系数(Papp)值最大,米诺地尔Papp值最小,中渗透性药物二甲双胍的Papp值大于雷尼替丁的Papp值,低渗透性药物甘露醇的Papp值与高渗透性药物相差较大,但与中渗透性药物相差不大;零渗透性药物荧光黄Papp值较小。结论:结合本研究得到的数据,本研究已初步建立了药物表观渗透系数与其对应的渗透性类别的相关性,可以为药物的BCS分类提供数据依据;如果待研究药物或化合物的Papp值≥米诺地尔的Papp值,可认为它是高渗透性药物。

关键词:[关键词] Caco-2细胞;生物药剂学分类系统;肠道渗透性;表观渗透系数

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Abstract:[Abstract] Objective: To investigate the intestinal permeability of different BCS classification drugs, and to determine the correlation between the intestinal permeability assessment system and its BCS classification in the Waiver of In Vivo Bioavailability and Bioequivalence Studies issued by CFDA. Methods: Caco-2 cell model was applicated to evaluate the effects of high permeability drugs (antipyrine, carbamazepine, phenytoin, theophylline, caffeine, propranolol, metoprolol, minoxidil), moderate permeability drugs (metformin, ranitidine), low permeability drugs (mannitol), zero osmotic drugs (lucifer yellow CH), and efflux drugs (digoxin, rhodamine 123) and their time-dependency. Results: The TEER values showed a good density of the cell model. Rhodamine 123 and digoxin showed their good efflux, which was obviously inhibited by the P-gp inhibitor verapamil, indicating the efflux capacityof the cell model. In experiments of high permeability drugs, the Papp of antipyrine value was the largest, and that of minoxidil value was the smallest. For moderate permeability drugs, the Papp value of metformin was greater than that of ranitidine. The Papp value of the low permeability drug mannitol was largely different from that of the high permeability drugs, but the difference with moderate permeability drugs was not so much. The Papp value of the zero permeability drug lucifer yellow CH was smaller. Conclusion: Based on the data obtained in this study, the correlation between the apparent osmotic coefficient of the drug and its corresponding BCS classification is established. If the Papp value of a drug or a compound to be studied is larger than that of minoxidil, it will be considered to be a high permeability drug.

Key words:[Key words] Caco-2 cell; biopharmaceutics classification system (BCS); intestinal permeability; permeability coefficient (Papp)

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