Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans

J Pharmacol Exp Ther. 1988 Mar;244(3):994-9.


Antipyrine and theophylline disposition was studied in healthy volunteer subjects in the control state while the subjects were taking verapamil (120 mg) orally four times daily or diltiazem (120 mg) orally three times daily. Both verapamil and diltiazem treatment decreased antipyrine clearance (verapamil, 42.5 to 30.1 ml/min, P less than .01; diltiazem, 41.7 to 29.9 ml/min, P less than .01), resulting in prolonged antipyrine half-life with no change in distribution volume. Fractional clearances of urinary antipyrine metabolites 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, norantipyrine and unchanged antipyrine were differentially changed by verapamil and diltiazem treatment. With verapamil treatment, 4-hydroxyantipyrine and norantipyrine fractional clearances were markedly decreased, with 3-hydroxymethylantipyrine slightly decreased and antipyrine unchanged. With diltiazem treatment, 3-hydroxymethylantipyrine was decreased, with no significant change in 4-hydroxyantipyrine, norantipyrine or antipyrine. Effect on theophylline clearance differed between verapamil treatment (57.7 to 44.7 ml/min; P less than .01) and diltiazem treatment (50.2 to 49.4 ml/min; N.S.), with prolonged theophylline half-life during verapamil treatment, no change in half-life during diltiazem treatment and distribution volume unchanged by either treatment. Fractional clearances of urinary theophylline metabolites 3-methylxanthine, 1-methyluricacid, 1,3-dimethyluricacid and unchanged theophylline reflected the differential plasma theophylline clearance. During verapamil treatment, 3-methylxanthine and 1,3-dimethyluricacid fractional clearances were decreased, with no change in 1-methyluricacid or theophylline. During diltiazem treatment, 1,3-dimethyluricacid fractional clearance was slightly decreased, and 3-methylxanthine, 1-methyluricacid and theophylline were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antipyrine / pharmacokinetics*
  • Cytochrome P-450 Enzyme Inhibitors
  • Diltiazem / pharmacology*
  • Drug Interactions
  • Female
  • Half-Life
  • Humans
  • Male
  • Metabolic Clearance Rate / drug effects
  • Theophylline / pharmacokinetics*
  • Verapamil / pharmacology*


  • Cytochrome P-450 Enzyme Inhibitors
  • Theophylline
  • Verapamil
  • Diltiazem
  • Antipyrine