EFFECT OF CYCLODEXTRINS ON PROTEIN-BINDING OF DRUGS - THE DIFLUNISAL HYDROXYPROPYL-BETA-CYCLODEXTRIN MODEL CASE

The binding of diflunisal to hydroxypropyl-beta-cyclodextrin (HPbetaCD ), bovine serum albumin (BSA), human serum albumin (HSA), normal human plasma, and mixed solutions of HPbetaCD/protein was studied at 25-deg rees-C, pH 7.4, by potentiometry using an electrode selective to diflu nisal. The experimental data for diflunisal/HPbetaCD fit well to the 1 :1 binding model. The binding of diflunisal with each of the studied p roteins was compatible with a model having two independent classes of binding sites. The binding of diflunisal in mixed solutions HPbetaCD/B SA, HPbetaCD/HSA, and HPbetaCD/plasma increased considerably when the HPbetaCD concentration was increased. The binding behavior of the two biomolecules in the mixed solutions of HPbetaCD/BSA or HPbetaCD/HSA wa s described with an ''additive'' model formulated on the basis of the estimates of the binding parameters of diflunisal derived from the sep arate experiments with each one of the binders tested. The lower than theoretical binding observed in HPbetaCD/plasma solutions was ascribed to the competitive displacement of diflunisal from the HPbetaCD cavit y by plasma cholesterol.