DRUG-BINDING TO GASTRIC MUCUS GLYCOPROTEINS

Absorption of drugs across any mucosal tissue may involve interactions with the mucus gel overlying the tissue. Drug binding to the mucus gl ycoproteins, in particular, can reduce the amount of free drug availab le for absorption. In order to evaluate the extent of drug binding to mucin, a purified model mucus system containing primarily the large gl ycoprotein fraction (400 kDa) of gastric mucus was developed for use i n drug binding studies. The extent of binding of six selected compound s (albuterol, rifampicin, p-amino-salicylic acid, isoniazid, pyrazinam ide, and pentamidine) to mucus glycoproteins was studied. The binding of each drug to a model plasma protein, bovine serum albumin (BSA), wa s also investigated. Binding studies were performed by diafiltration, which combines characteristics of equilibrium dialysis and ultrafiltra tion in a continuous system. All the compounds selected showed affinit ies of the same order of magnitude to mucin despite being chemically d issimilar and exhibiting differing ionization states. This suggests th at binding to gastric mucus glycoproteins is non-specific in nature wi th similar types of binding forces involved in the binding of all the compounds tested. Results also showed that the drug-protein associatio n constants for BSA and mucin were of the same order of magnitude only for drugs with low binding affinities. When the binding constants to BSA were moderate to high, the corresponding drug binding constants to mucin were lower by at least one order of magnitude. Based on these r esults, it can be concluded that the binding behavior of drugs to gast ric mucin is non-specific in nature with binding constants of a low ma gnitude. BSA cannot be used to estimate binding to mucin, especially w hen the drug exhibits moderate to high affinity for BSA.