Binding of drugs with a quaternary ammonium group to alpha-1 acid glycoprotein and asialo alpha-1 acid glycoprotein.

The interaction of eight mono- and four bisquaternary ammonium compounds with alpha-1 acid glycoprotein and its desialylated derivative was investigated. Protein binding was performed in vitro by equilibrium dialysis at 37 degrees C. The simple monoquaternary ammonium compounds tributylmethylammonium, tripropylmethylammonium, triethylmethylammonium and procainethobromide were not appreciably bound (unbound fraction greater than 0.99). Excellent negative correlations of unbound fraction and the log of the octanol/Krebs' partition coefficient were obtained for thiazinamium, N-methylimipramine, N-methyldeptropine and d-tubocurarine, both for alpha-1 acid glycoprotein (r = -0.99) and asialo alpha-1 acid glycoprotein (r = -0.94). Bisquaternary ammonium compounds, with the exception of hexafluorenium, were only poorly bound. Our binding data on N-methyl-deptropine, N-methylimipramine and thiazinamium reveal that these compounds are more avidly bound to alpha-1 acid glycoprotein than to albumin, in spite of their polar character. The interaction of N-methyldeptropine with alpha-1 acid glycoprotein was studied in more detail. Scatchard plots revealed the presence of two classes of binding sites. N-Methyldeptropine could effectively be displaced by imipramine from its high-affinity binding site. This points to the presence of a common high-affinity binding site for tertiary and quaternary ammonium compounds on alpha-1 acid glycoprotein.