The Influence of H₂‐Receptor Antagonists on Steady‐State Concentrations of Propranolol and 4‐Hydroxypropranolol

Abstract: Twelve healthy male volunteers were treated with 1200 mg/day cimetidine, 300 mg/day ranitidine, or no H₂‐receptor antagonist (control) tor seven days in a sequence determined by Latin‐square design. Each treatment period was separated by a seven‐day washout. On the third day of each treatment period, 80 mg propranolol every 12 hours for nine doses was initiated. Whole blood concentrations of propranolol and 4‐hydroxypropranolol were measured at 12 time points during the 12‐hour period following administration of the last propranolol dose. Heart rate was measured before each blood sample was withdrawn. Cimetidine treatment was associated with a 47 per cent increase in the area under the propranolol concentration‐time curve and a 17 per cent increase in elimination half‐life of propranolol. Ranitidine had no significant effect on the concentration‐time profile of propranolol. There were no significant differences in the 4‐hydroxypropranolol pharmacokinetic parameters during any of the treatments. There was, however, a significant decrease in the average 4‐hydroxypropranolol‐to‐propranolol steady‐state concentration ratio during the cimetidine treatment. There was no significant difference in heart rate between any of the treatments. The elevation of propranolol concentrations during cimetidine treatment is likely due to metabolic inhibition by cimetidine. 1984 American College of Clinical Pharmacology