The inhibition of rat hepatic microsomal propranolol metabolism by a covalently bound reactive metabolite.
Repetitive oral propranolol administration to rats (100 mg/kg/day for 5 days) resulted in an 80% inhibition of propranolol Type I spectral binding capacity. This paralleled a similar reduction in the microsomal metabolism of propranolol when incubated at low substrate concentrations (less than 2 microM). Propranolo was converted both in vitro and in vivo by a microsomal mixed function oxidase to a reactive intermediate metabolite capable of covalently binding with microsomal macromolecules. We propose that covalent binding of the intermediate to the catalytic site of a form(s) of cytochrome P-450 that metabolizes propranolol would account for the marked inhibition of propranolol metabolism observed following propranolol pretreatment.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011433:Propranolol / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D005978:Glutathione