DIFFUSION OF DRUGS IN NATIVE AND PURIFIED GASTROINTESTINAL MUCUS

The mucus layer covering the surface of the gastrointestinal tract may act as a barrier to drug absorption. The aim of this investigation wa s to study the self-diffusion coefficients of model drugs with differe nt physicochemical properties in gastrointestinal mucus. An in vitro m ethod was used to determine the self-diffusion coefficients of radiola beled model drugs in different diffusion media. Glucosamine, mannitol, glucuronic acid, glucose, metoprolol, antipyrine, propranolol, hydroc ortisone, and testosterone, which display large differences in charge and octanol/water distribution ratios (K), were used as model drugs. T he diffusion coefficients of model drugs were compared in phosphate bu ffer (PB), native pig intestinal mucus (PIM), and purified pig gastric mucin (PPGM). PIM was not purified and therefore contained all the or iginal components of native mucus, whereas PPGM contained only high mo lecular weight mucin molecules. Charge had only minor effects on the d iffusion coefficients of the model drugs. Lipophilicity, however, had a much larger effect; the largest decrease in diffusion coefficient, 5 8%, was observed for testosterone in PIM. A negative relationship betw een the diffusion coefficient and log K was observed in PIM, but no re lationship was observed in PPGM and PB. In contrast, the diffusion coe fficients for two larger molecules of comparable size, the lipophilic peptide cyclosporin and the hydrophilic peptide D-arginine vasopressin , were markedly reduced in PIM. In conclusion, the most important phys icochemical characteristic influencing the diffusion coefficient of mo st drugs in gastrointestinal mucus appears to be lipophilicity, wherea s molecular size appears to have more influence for larger peptide dru gs.