上海交通大学学报（医学版）

›› 2012, Vol. 32 ›› Issue (12): 1605-.doi: 10.3969/j.issn.1674-8115.2012.12.018

• 论著（基础研究） • 上一篇    下一篇

应用Caco-2细胞模型观察介质pH和氨氯地平对替米沙坦跨膜吸收转运的影响

黄 霞1, 江 涛2, 翟 青3   

  1. 1.上海交通大学 医学院附属瑞金医院预防保健科, 上海 200025； 2.上海Waters科技有限公司, 上海 201203； 3.复旦大学附属肿瘤医院药剂科, 上海 200032
  • 出版日期:2012-12-28 发布日期:2012-12-31
  • 通讯作者: 翟 青, 电子信箱: zhaiqing63@126.com。
  • 作者简介:黄 霞（1962—）, 女, 副主任医师, 学士；电子信箱: huangx1234@yahoo.com。

Influence of pH and amlodipine on transmembrane uptake transport of telmisartan in Caco-2 cell model

HUANG Xia1, JIANG Tao2, ZHAI Qing3   

  1. 1.Department of Health Care, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China；2.Shanghai Waters Science Company, Shanghai 201203, China；3.Department of Pharmacy, Cancer Hospital, Fudan University, Shanghai 200032, China
  • Online:2012-12-28 Published:2012-12-31

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摘要：

目的 探讨介质pH值和常用合并用药氨氯地平对血管紧张素Ⅱ受体（AT1型）拮抗剂替米沙坦跨膜吸收转运的影响。方法 体外培养人结直肠癌Caco-2细胞，通过细胞形态观察、跨上皮细胞电阻(TEER)测定和荧光黄通透性实验验证Caco-2细胞单层完整性；通过ATP酶活性测定和双向转运实验分析替米沙坦是否外排糖蛋白(P-gp)底物；观察改变介质pH及合并使用氨氯地平时对替米沙坦跨膜吸收转运的影响。结果 建立的Caco-2细胞单层完整，适用于转运实验。替米沙坦ATP酶活性与空白对照ATP酶活性的比值为1.73，双向转运实验结果显示外排比率为4.53。随着pH值(8.0～5.0)的降低，替米沙坦吸收表观通透性逐渐增强，跨膜吸收转运呈现明显的pH依赖性。在pH 7.4且合并氨氯地平时，替米沙坦吸收表观通透性明显增强。结论 P-gp可能参与替米沙坦跨膜分泌转运，介质pH酸性环境和氨氯地平可易化替米沙坦跨膜吸收转运。

关键词: 替米沙坦, 氨氯地平, Caco-2细胞, 药物转运

Abstract:

Objective To investigate the influence of pH and commonly coadministered amlodipine on the transmembrane uptake transport of telmisartan. Methods Human colorectal cancer Caco-2 cells were cultured in vitro, and its monolayer integrity was confirmed by cell morphology, transepithelial electrical resistance (TEER) measurement and lucifer yellow permeability test. ATPase activity measurement and bidirection permeability experiment were performed to analyse whether telmisartan was a substrate of P-glycoprotein (P-gp). The influence of pH and amlodipine on the transmembrane uptake transport of telmisartan was assessed. Results The cultured Caco-2 cell monolayer exhibited tight junction, which was applicable for transport study. The ratio of ATPase activity of telmisartan to that of blank control was 1.73, and the efflux rate was 4.53 in the bidirection permeability experiment. With the decrease of pH from 8.0 to 5.0, the transmembrane uptake transport of telmisartan gradually increased in a pH-dependent manner. The transmembrane uptake was significantly enhanced at pH of 7.4 with coadministration of amlodipine. Conclusion The transmembrane transport of telmisartan may be mediated via P-gp, and its uptake transport is influenced by both pH and coadministration of amlodipine.

Key words: telmisartan, amlodipine, Caco-2 cell, drug transport