Further elucidation of pharmacokinetic interaction between diltiazem and warfarin

A. M. Stoysich, B. D. Lucas, Syed M. Mohiuddin, Daniel E. Hilleman

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Abstract

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 AUC(0-6,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.

Original languageEnglish
Pages (from-to)56-60
Number of pages5
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume34
Issue number2
StatePublished - 1996

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Pharmacokinetics
Diltiazem
Warfarin
International Normalized Ratio
Protein Binding
Dialysis
Metabolism
Cross-Over Studies
Anticoagulants
Area Under Curve
Healthy Volunteers
Blood
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology (medical)

Cite this

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abstract = "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 AUC(0-6,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.",
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N2 - 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 AUC(0-6,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.

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