FURTHER ELUCIDATION OF PHARMACOKINETIC INTERACTION BETWEEN DILTIAZEM AND WARFARIN

Diltiazem and warfarin are both highly protein-bound providing the opp ortunity for a protein-binding displacement interaction to occur. Addi tionally, diltiazem has demonstrated the ability to inhibit the metabo lic clearance of hepatically cleared drugs (e.g. warfarin). We evaluat ed these pharmacokinetic mechanisms for a potential interaction. A sin gle warfarin 25 mg oral dose was given with and without oral diltiazem 30 mg 3 times daily to 20 healthy male volunteers in a randomized cro ssover design with a washout period of at least 6 days. Serial blood s amples for INRs and free and total warfarin concentrations were obtain ed over 144 hours after each warfarin dose. Free fraction was extracte d by equilibrium dialysis and free and total warfarin concentrations w ere analyzed by HPLC. Anticoagulation was assessed using AUC(0-6,INR) (days). Diltiazem was found not to potentiate anticoagulation by warfa rin. Furthermore, warfarin protein binding displacement did not occur. Diltiazem inhibited both free and total warfarin clearance, though no t statistically significant. Although slightly inhibiting metabolism o f warfarin, based on warfarin clearance, diltiazem did not increase wa rfarin's anticoagulant effect making it an acceptable addition to ther apy if required.