Massive propranolol metabolite retention during maintenance hemodialysis

Eight outpatients on long-term hemodialysis receiving propranolol therapy were studied on a nondialysis day, 11 +/- 1 hr after the last dose. Steady-state daily dosage of propranolol averaged 225 +/- 36 mg (range, 80 to 400). Plasma concentrations of propranolol and three of its metabolites were measured by gas chromatography--mass spectrometry (x +/- SEM): propranolol, 47 +/0 17 ng/ml; propranolol glucuronide, 2.119 +/0 597 ng/ml; 4-hydroxypropranolol glucuronide, 789 +/- 149 ng/ml; and naphthoxylactic acid, 4,357 +/- 727 ng/ml. The plasma levels of these metabolites were 18, 20, and 29 times, respectively, as high as in patients with normal renal function and correlated well with the dose of propranolol. The total concentration of these metabolites exceeded the concentration of propranolol to 239 times (range 74 to 476). Four long-term hemodialysis patients on propranolol were hospitalized to ensure compliance. Plasma levels of propranolol and of the three metatolites were followed during a dosage interval. Plasma propranolol correlated well with dose (r = 0.94) and declined with approximately normal half-lifes of 3.2 to 5.4 hr. There was little variation in the extremely high plasma levels of the three metabolites during a dosage interval. The total metabolite to propranolol plasma concentration ratio in these four patients ranged from 109 to 705. The correlation between total metabolite concentrations and propranolol dose was striking (r = 0.997). Massive retention of propranolol metabolites occurs uniformly in uremia, is highly predictable from the dose, and could have important clinical implications.