Selective inhibition of warfarin metabolism by diltiazem in humans

D. R. Abernethy, L. S. Kaminsky, T. H. Dickinson

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32 Scopus citations


Healthy men were administered i.v. racemic warfarin, S-warfarin or R-warfarin on two occasions, once in the drug-free state and once during concomitant administration of oral diltiazem 120 mg three times daily. Blood samples for determination of plasma warfarin and diltiazem concentrations, the prothrombin time and complete urine collections were obtained for determination of urinary excretion of dehydrowarfarin, 4'-hydroxywarfarin, 6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin and unchanged parent drug for 216 h after each dose. Concurrent diltiazem administration decreased total racemic warfarin clearance (± S.D.) [3.60 ± 0.99 (control) versus 3.19 ± 0.86 (diltiazem) ml/min; P < .05]. Disposition of the more potent anticoagulant S-warfarin was not altered by diltiazem treatment. In contrast total clearance of R-warfarin was decreased [3.47 ± 1.10 (control) versus 2.77 ± 0.92 ml/min; P < .05]. No change in the area under the prothrombin time versus time after warfarin administration curve was associated with diltiazem treatment for any warfarin trial. Inhibition of R-warfarin by diltiazem was regio selective for metabolites as determined by fractional clearance of urinary metabolites. R-6-hydroxywarfarin clearance (± S.E.) [29.5 ± 7.2 (control) versus 15.7 ± 2.8 ml/h; P < 0.05] and R-8 hydroxywarfarin clearance [21.1 ± 3.6 (control) versus 11.2 ± 2.0 ml/h; P < .05] were selectively decreased with no significant change in the urinary clearance of R-dehydro, R-4-hydroxy and R-7-hydroxywarfarin. Urinary clearance of unchanged R-warfarin was also decreased during diltiazem administration. Diltiazem inhibits warfarin disposition in humans in a stereospecific and regiospecific manner.

Original languageEnglish (US)
Pages (from-to)411-415
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1991

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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