TY - JOUR T1 - The inhibitory effect of propranolol pretreatment on its own metabolism in the rat. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 575 LP - 581 VL - 218 IS - 3 AU - D W Schneck AU - J F Pritchard Y1 - 1981/09/01 UR - http://jpet.aspetjournals.org/content/218/3/575.abstract N2 - Repetitive oral administration of propranolol to rats (100 mg/kg/day for 5 days) resulted in a marked inhibition of hepatic microsomal metabolism of propranolol when incubated at low initial substrate concentrations (less than 2 microM). Associated with the inhibition of propranolol metabolism was a significant reduction in metabolites derived from naphthalene ring oxidation and an increased formation of N-desisopropylpropranolol. In vivo studies after propranolol pretreatment resulted in: an increased hepatic concentration and an increased systemic availability of propranolol; a decreased hepatic and plasma concentration of polar metabolites; and an increased plasma concentration of metabolites derived from propranolol N-dealkylation. Propranolol was converted both in vitro and in vivo by a hepatic microsomal mixed-function oxidase to a reactive metabolite capable of covalently binding with microsomal macromolecules. We propose that selective covalent binding of the reactive intermediate to the molecular form of cytochrome P-450 that ring hydroxylates propranolol would account for the marked inhibition of propranolol metabolism in vitro and for the increased systemic availability of propranolol in vivo after pretreatment. ER -