Interaction of Ketotifen Fumarate with Anhydrous Theophylline in Simulated Gastric and Intestinal Media and Effect on Protein Binding

Purpose: The purpose of the present study was to investigate interaction between ketotifen fumarate and anhydrous theophylline in aqueous media of various pH.
Methods: By using Job’s continuous-variation analysis and Ardon’s spectrophotomeric methods, the values of stability constants of theophylline with ketotifen were determined at a fixed temperature (37 ⁰C) at each of the medium pH. In vitro study of protein (bovine albumin, fraction v) binding was carried out by equilibrium dialysis method at pH 7.4 to ascertain the influence of ketotifen on the protein binding of theophylline.
Results: Stability constant, ranging between 5.07 and 6.35, were derived from Ardon’s plot, indicating that complexes formed, as a result of interaction between the drugs, were comparatively stable. However, following theophylline interaction with ketotifen, stability constant was <1 at gastric pH (0.4 and 2.0) and 4.12 at intestinal pH. (6.0)The highest degree of protein binding by ketotifen was 98 % and the lowest 90 %. For theophylline, the highest and lowest degrees of protein binding were 90 and 85 %, respectively.
Conclusion: Concurrent administration of ketotifen and theophylline would result in the formation of a stable complex and this is likely to reduce the therapeutic activities of both drugs. With regard to protein binding, the concentration of theophylline increased with decrease in ketotifen concentration.

Keywords
Stability constant, Job’s method, Ardon’s method, Ketotifen fumarate, Complex formation, Protein binding, Theophylline