Larhed A W, Artursson P, Björk E
Dept. of Pharmacy/Division of Pharmaceutics, Uppsala University, Sweden.
Pharm Res. 1998 Jan;15(1):66-71. doi: 10.1023/a:1011948703571.
Mucus, a potential diffusional barrier to drug absorption, is a complex mixture of mucin and other components. The objective of this study was to investigate the composition of native pig intestinal mucus (PIM) and the influence of identified mucus components on drug diffusion.
The mucus components were separated by CsCl-density gradient centrifugation and further analyzed. The self-diffusion coefficients of mannitol, metoprolol, propranolol, hydrocortisone, and testosterone, ranging in lipophilicity from logK = -3.1 to logK = 3.3, were determined, using a small scale tracer technique. The diffusion of drugs in PIM, in solutions or dispersions of individual mucus components, and in an artificial mucus model (MLPD) reconstituted from the major mucus components mucin, lipids, protein, and DNA was compared.
The dry weight of pig intestinal mucus contained (%, w/w); mucin (5%), lipids (37%), proteins (39%), DNA (6%), and unidentified materials. The most commonly occurring lipids were free fatty acids, cholesterol, and phospholipids while the most common protein was serum albumin. In PIM, but not in the purified pig gastric mucin (PPGM) solution, the diffusion of the lipophilic drugs metoprolol, propranolol, hydrocortisone, and testosterone was reduced compared to that of the hydrophilic drug mannitol. The diffusion of the lipophilic drugs was also significantly reduced in a dispersion of identified mucus lipids compared to that of mannitol. The diffusion in MLPD was similar to that in PIM for mannitol, propranolol, hydrocortisone, and testosterone, but somewhat lower for metoprolol.
Lipids, rather than mucin glycoproteins, are a major component which contributes to reduced diffusion of drugs in native intestinal mucus. The results suggest that reconstituted artificial mucus models are interesting alternatives to native mucus models.
黏液是药物吸收的潜在扩散屏障，是黏蛋白和其他成分的复杂混合物。本研究的目的是研究天然猪肠黏液（PIM）的组成以及已鉴定的黏液成分对药物扩散的影响。
通过CsCl密度梯度离心分离黏液成分并进一步分析。使用小规模示踪技术测定了甘露醇、美托洛尔、普萘洛尔、氢化可的松和睾酮的自扩散系数，其亲脂性范围为logK = -3.1至logK = 3.3。比较了药物在PIM、单个黏液成分的溶液或分散体以及由主要黏液成分黏蛋白、脂质、蛋白质和DNA重构的人工黏液模型（MLPD）中的扩散情况。
猪肠黏液的干重包含（％，w/w）；黏蛋白（5％）、脂质（37％）、蛋白质（39％）、DNA（6％）和未鉴定物质。最常见的脂质是游离脂肪酸、胆固醇和磷脂，而最常见的蛋白质是血清白蛋白。在PIM中，但在纯化的猪胃黏蛋白（PPGM）溶液中未观察到，与亲水性药物甘露醇相比，亲脂性药物美托洛尔、普萘洛尔、氢化可的松和睾酮的扩散减少。与甘露醇相比，在已鉴定的黏液脂质分散体中亲脂性药物的扩散也显著降低。甘露醇、普萘洛尔、氢化可的松和睾酮在MLPD中的扩散与在PIM中的扩散相似，但美托洛尔的扩散略低。
脂质而非黏蛋白糖蛋白是导致天然肠黏液中药物扩散减少的主要成分。结果表明，重构的人工黏液模型是天然黏液模型的有趣替代物。
