THE INFLUENCE OF INTESTINAL MUCUS COMPONENTS ON THE DIFFUSION OF DRUGS

Purpose. Mucus, a potential diffusional barrier to drug absorption, is a complex mixture of mucin and other components. The objective of thi s study was to investigate the composition of native pig intestinal mu cus (PIM) and the influence of identified mucus components on drug dif fusion. Methods. The mucus components were separated by CsCl-density g radient centrifugation and further analyzed. The self-diffusion coeffi cients of mannitol, metoprolol, propranolol, hydrocortisone, and testo sterone, ranging in lipophilicity from logK = -3.1 to logK = 3.3, were determined, using a small scale tracer technique. The diffusion of dr ugs 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. Result s. 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, cholestero l, 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, hydrocorti sone, and testosterone was reduced compared to that of the hydrophilic drug mannitol. The diffusion of the lipophilic drugs was also signifi cantly 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. Conclusions. Lipids, rather than mucin glycopro teins, are a major component which contributes to reduced diffusion of drugs in native intestinal mucus. The results suggest that reconstitu ted artificial mucus models are interesting alternatives to native muc us models.