The limiting role of mucus in drug absorption: Drug permeation through mucus solution
The limiting role of mucus in drug absorption: Drug permeation through mucus solution
复制标题
DOI：
10.1016/0378-5173(95)04120-6
复制
发表时间：
1995-12-29
影响因子：
5.8
通讯作者：
Donovan, MD
中科院分区：
文献类型：
--
作者：
Bhat, PG;Flanagan, DR;Donovan, MD
已经开发了主要含有粘液的大的400 kDa糖蛋白部分的纯化模型体外粘液系统，用于药物渗透性和药物结合研究。研究了蛋白质溶液（牛血清白蛋白（BSA）或纯化猪胃粘液）对五种药物渗透行为的影响。选择的药物是异烟肼、喷他脒、利福平、对氨基水杨酸和吡嗪酰胺，所有这些药物都可能以肺气雾剂的形式递送。渗透性研究中包括BSA，以与先前获得的关于其相对于BSA与粘蛋白的结合行为的数据进行比较。在Side-Bi-Side（R）扩散装置中使用具有用于粘蛋白或其它溶液的3 mm腔室的定制膜保持器来测量药物通过溶液的渗透。计算了串联屏障系统中每个屏障的表观渗透系数，其中蛋白质溶液是屏障之一。与空白缓冲液相比，蛋白质溶液显著降低了所研究药物的渗透性。在蛋白质存在下，化合物的滞后时间和稳态通量都发生了变化，表明影响渗透性的不仅仅是蛋白质结合。对于在吸收或作用之前必须穿过任何粘膜表面的所有化合物，需要考虑渗透系数的这种降低。
A purified model in vitro mucus system containing primarily the large, 400 kDa glycoprotein fraction of mucus has been developed for use in drug permeability and drug binding studies. The effect of protein solutions, either bovine serum albumin (BSA) or purified porcine gastric mucus, on the permeability behavior of five drugs was studied. The drugs chosen were isoniazid, pentamidine, rifampicin, p-aminosalicylic acid, and pyrazinamide, all of which can be potentially delivered as pulmonary aerosols. BSA was included in the permeability studies for comparison with previously obtained data regarding their binding behaviors to mucin relative to BSA. A custom membrane holder with a 3 mm chamber for mucin or other solutions was used in a Side-Bi-Side(R) diffusion apparatus to measure drug permeation through the solutions. Apparent permeability coefficients were calculated for each barrier in the series barrier system, with a protein solution being one of the barriers. The protein solutions significantly reduced the permeability of the drugs studied compared with their permeability through blank buffer solution. Both the lag time and the steady-state flux of the compounds were altered in the presence of protein indicating that there is more than protein binding affecting permeability. Such reductions in permeability coefficients need to be considered for all compounds that must traverse any mucosal surface prior to absorption or action.