Influence of midazolam on the protein binding of ketorolac

Background: An important aspect of a drug's biodisposition profile is the e xtent to which it binds to plasma proteins. Objective: The purpose of this laboratory investigation was to assess the p otential for an in vitro drug-drug protein displacement interaction between ketorolac and midazolam. Methods: The protein binding of ketorolac and midazolam, individually and i n combination, were determined in (1) human serum, (2) human albumin soluti on, and (3) human alpha(1)-acid glycoprotein solution using ultrafiltration technology. Total and free concentrations of ketorolac were quantitated by liquid chromatography, whereas those of midazolam were quantitated by gas chromatography. Drug concentrations used in this in vitro study were select ed from published data reflecting realistic plasma drug concentrations obse rved after aggressive clinical drug dosing. Results: Both ketorolac and midazolam are extensively bound to serum protei n. Over the concentration range studied, ketorolac bound primarily to album in whereas midazolam bound extensively to albumin and alpha(1)-acid glycopr otein. Under the conditions of the present in vitro study, neither ketorola c nor midazolam demonstrated any effect on the extent to which either drug was bound in the 3 systems studied. Conclusions: The in vitro data derived in this study suggest that when pres ent together, neither midazolam nor ketorolac influences the overall extent of protein binding of the other. Drug protein binding data derived in vitr o should be cautiously extrapolated to in vivo conditions.