Studies on the contribution of active metabolites to the anticonvulsant effects of propranolol.
The anticonvulsant activity of propranolol and two selected metabolites, propranolol glycol and N-desisopropylpropranolol were compared in mice against 4 types of experimentally induced seizures: pentylenetetrazol, strychnine, low frequency and maximal electroshock. Both metabolites possessed significant anticonvulsant activity with propranolol glycol being 1/2 to 1/3 as potent and N-desisopropylpropranolol being 1/6 as potent as propranolol. The possible contribution of these two active metabolites to the acute anticonvulsant efficacy of propranolol was assessed in time course studies. Maximal anticonvulsant activity occurred between 2.5--10 min after propranolol (5-20 mg/kg, i.v.) and was significantly diminished after 30 min. Following propranolol, brain levels of both metabolites were extremely low ( less than 10 ng/g) at the onset of anticonvulsant action and reached peak levels between 15-30 min at which time anticonvulsant activity was already declining. In contrast, brain levels of propranolol were similar in time course to that observed for its anticonvulsant effect and there was significant positive correlation between these two parameters in 3 of the 4 seizure models. These data indicate that although these two metabolites are pharmacologically active, they do not contribute significantly to the acute anticonvulsant actions observed after propranolol administration.
D000818:Animals; D000927:Anticonvulsants; D001923:Brain Chemistry / Q000187:drug effects; D004597:Electroshock; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D011433:Propranolol / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology*; D013331:Strychnine / Q000037:antagonists & inhibitors; D013997:Time Factors
D000927:Anticonvulsants; D011433:Propranolol; D013331:Strychnine; D010433:Pentylenetetrazole