Effect of temperature and fat content on the binding of hydrochlorothiazide and chlorothiazide to milk

The binding of hydrochlorothiazide and chlorothiazide to milk has been measured. Experiments were carried out at 5, 15, 25, and 37 degrees C on bovine milk samples with fat contents of 0.75, 1.70, and 3.50%, using a wide range of drug concentrations to mimic concentrations encountered when a drug-milk freeze-dried system is utilized. Binding experiments with a 2.6% solution of casein were also carried out at the same temperature and concentration range of drugs. The binding to milk and casein was found to be not dependent on the concentration of drugs. The fat content of milk had no significant effect on the binding of both drugs. Higher binding was observed at lower temperatures than at higher temperatures for both drugs examined. The binding of both drugs to casein at 37 degrees C agrees fairly well with the corresponding binding to all types of milk at 37 degrees C. The potential significance of the findings in respect to preparation and in vivo delivery of drugs from drug-milk formulations is discussed.