Effect of alterations in drug metabolism on epinephrine-induced cardiac arrhythmias in rabbits exposed to methylchloroform.
Control rabbits or those treated with the drug-metabolism inducer, phenobarbitol, or the inhibitors, 2-diethylaminoethyl-2,2-diphenylvalerate-HCI (SKF-525A) or 2,4-dichloro-6-phenylphenoxyethyldiethyl-amine-HBr (Lilly 18947) were exposed to 5600 ppm methylchloroform in an inhalation chamber under dynamic airflow conditions. Phenobarbital treatment slightly decreased blood levels of methylchloroform and the incidence of cardiac arrhythmias. The two inhibitors decreased the metabolism of methylchloroform and increased the incidence of arrhythmias. Methylchloroform rather than its metabolites appeared responsible for the arrhythmias. This arrhythmogenicity was altered by agents which affect the disposition and hence the blood levels of the compound.
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001713:Biphenyl Compounds / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System; D004048:Diethylamines / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology*; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000097:blood; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011817:Rabbits; D014238:Trichloroacetic Acid / Q000097:blood; D014240:Trichloroethanes / Q000097:blood / Q000633:toxicity*
D000963:Antimetabolites; D001713:Biphenyl Compounds; D004048:Diethylamines; D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; C002109:Lilly 18947; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C005849:2,2,2-trichloroethanol; D004837:Epinephrine; D010634:Phenobarbital