Further elucidation of pharmacokinetic interaction between diltiazem and warfarin

Diltiazem and warfarin are both highly protein-bound providing the opportunity for a protein-binding displacement interaction to occur. Additionally, diltiazem has demonstrated the ability to inhibit the metabolic clearance of hepatically cleared drugs (e.g. warfarin). We evaluated these pharmacokinetic mechanisms for a potential interaction. A single 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 crossover design with a washout period of at least 6 days. Serial blood samples for INRs and free and total warfarin concentrations were obtained over 144 hours after each warfarin dose. Free fraction was extracted by equilibrium dialysis and free and total warfarin concentrations were analyzed by HPLC. Anticoagulation was assessed using AUC0-6,INR (days). Diltiazem was found not to potentiate anticoagulation by warfarin. Furthermore, warfarin protein binding displacement did not occur. Diltiazem inhibited both free and total warfarin clearance, though not statistically significant. Although slightly inhibiting metabolism of warfarin, based on warfarin clearance, diltiazem did not increase warfarin's anticoagulant effect making it an acceptable addition to therapy if required.