PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: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.
Authors: Xavier J H Pepin; James E Huckle; Ravindra V Alluri; Sumit Basu; Stephanie Dodd; Neil Parrott; Arian Emami Riedmaier Journal: AAPS J Date: 2021-01-04 Impact factor: 4.009