The effect of chronic felbamate administration on anticonvulsant activity and hepatic drug-metabolizing enzymes in mice and rats.
The possibility of tolerance development from chronic administration of felbamate (FBM) was investigated in mice and rats. Chronic administration (15 days) of FBM (150 mg/kg i.p.) in mice had no significant effect on either intravenous pentylenetetrazol (PTZ) seizure threshold or hexobarbital sleep time; however, hexobarbital sleep time was significantly increased after a single dose. Chronic administration (5-7 days) of FBM (48 or 95 mg/kg orally) in rats also had no significant effect on either maximal electroshock seizure activity or hexobarbital sleep time. Chronic administration of FBM at 238 mg/kg slightly decreased anti-subcutaneous PTZ activity in chronically treated rats (one of eight protected) as compared with those receiving only a single dose (three of eight protected), but there was no significant change in hexobarbital sleep time. Chronic treatment of rats for 7 days with 48 mg/kg had no significant effect on any hepatic parameters. However, 95 or 238 mg/kg of FBM significantly increased p-nitroanisole O-demethylase activity. It is concluded that the increased hexobarbital sleep time induced by an acute dose of FBM reflects the CNS-depressant effect of the substance. The increased p-nitroanisole O-demethylase activity observed after chronic administration may be indicative of some liver microsomal induction. Overall, FBM in doses ranging from 48 to 238 mg/kg appears to have minimal potential for tolerance development.
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004597:Electroshock; D004827:Epilepsy / Q000378:metabolism*; D000078328:Felbamate; D006591:Hexobarbital / Q000494:pharmacology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D010433:Pentylenetetrazole; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; C026048:4-nitroanisole O-demethylase; D010090:Oxidoreductases, O-Demethylating; D009251:NADPH-Ferrihemoprotein Reductase; D010433:Pentylenetetrazole; D000078328:Felbamate