Propranolol glucuronide cumulation during long-term propranolol therapy: a proposed storage mechanism for propranolol.

The comparative disposition of propranolol glucuronide (PG) and propranolol was determined in 35 patients with hypertension or coronary artery disease during initiation of propranolol therapy, during steady-state conditions, and after discontinuation of propranolol (dose range, 40 to 960 mg daily, every 6 hr). The 2.3-fold PG cumulation in plasma was identical to propranolol cumulation. PG plasma levels were about 4 times as high as propranolol levels over the whole dose range. Unexpectedly slow terminal elimination rate of propranolol (t1/2 approximately 16 to 24 hr) on discontinuation of propranolol appeared to be related to equally slow PG elimination. PG and propranolol could be detected in plasma and urine up to 3 to 5 days after propranolol discontinuation. The PG formed in man was deconjugated to propranolol in the dog after intravenous administration, suggesting that PG may serve as a storage pool for propranolol. Observations consistent with systemic and enteric deconjugation of PG, including enterohepatic recirculation, may, at least in part, explain the observed propranolol cumulation as well as the slow elimination of propranolol after its discontinuation. PG renal clearance (29 to 70 ml/min) and PG plasma levels were highly dependent on glomerular filtration rate, suggesting that PG may cumulate abnormally in patients with severe renal disease.