Effect of chronic caffeine administration on theophylline concentrations required to produce seizures in rats.
Caffeine as well as the antiasthmatic drug theophylline can cause seizures when administered to humans or animals in excessive doses. Studies on rats have shown rapid development of functional tolerance to caffeine-induced seizures whereas repeated pretreatment with theophylline had no significant effect on the theophylline concentrations required to produce seizures. The purpose of this investigation was to determine whether chronic exposure to caffeine can affect susceptibility to the convulsant effect of theophylline. Rats received caffeine, 40 mg/kg, or solvent twice a day for 7 days as an intravenous injection. On the eighth day, theophylline was infused intravenously until the onset of maximal seizures. At this pharmacologic end point, rats pretreated with caffeine had significantly higher theophylline concentrations in the brain and cerebrospinal fluid than did control (solvent-pretreated) animals. Although the concentration differences were relatively small (approximately 11%), they demonstrate in principle the development of caffeine-induced tolerance to the neurotoxic effect of theophylline. Additional experiments showed that the caffeine effect on theophylline neurotoxicity is not acutely mediated by paraxanthine, a major metabolite of caffeine.
Zhi
J G
JG
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst 14260.
Levy
G
G
D000818:Animals; D002110:Caffeine / Q000008:administration & dosage* / Q000097:blood; D004347:Drug Interactions; D004361:Drug Tolerance; D007700:Kinetics; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012640:Seizures / Q000139:chemically induced*; D013805:Theobromine / Q000097:blood; D013806:Theophylline / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid
D002110:Caffeine; D013806:Theophylline; D013805:Theobromine; C021183:1,7-dimethylxanthine