Toxicity of theophylline depends on plasma concentration by single and also repeated dosing in rats.
The purpose of this study was to evaluate the relationship between the in vivo toxicity and plasma concentration of theophylline. Theophylline was administered intravenously in single doses ( 50, 100, 150 and 200 mg kg(-1)once a day) or repeated doses (12.5, 25 and 90 mg kg(-1)/day for 28 days) in rats. Plasma concentrations of theophylline increased dose-dependently in both single and repeated doses, and there were no differences due to effects of 28-times repeated administration. Neither single dose at 50 mg kg(-1)nor repeated dose at 12.5 mg kg(-1)/day injections of theophylline showed toxic signs, in which plasma concentrations of theophylline were less than 110 and 22.5 microg ml(-1), respectively. Theophylline induced myocardial fibrosis in 25 mg kg(-1)/day and more treated groups: in which plasma concentrations of theophylline were more than 50 microg ml(-1). At doses of 100 mg kg(-1)(single) and 90 mg kg(-1)/day (repeated), theophylline caused tachypnea and excitement of movement. Each theophylline concentration in plasma was more than 194 microg ml(-1)in single 100 mg kg(-1)and 162 microg ml(-1)in repeated 90 mg kg(-1)/day injections, respectively. Death was observed at a dose of 200 mg kg(-1), in which the plasma concentration of theophylline was more than 264 microg ml(-1). Moreover, the recovery period from signs of toxic poisoning to normality in the 200 mg kg(-1)treated group was greater than that in the 150 mg kg(-1)and less treated groups. The results indicated that the in vivo toxicity of theophylline is highly dependent on plasma concentrations in rats which received single and also repeated doses of theophylline.
Onodera
K
K
Department of Dental Pharmacology, Okayama University Dental School, Okayama 700-8525, Japan. onoderak@md.okayama-u.ac.jp
Shibata
M
M
Kojima
J
J
Wachi
M
M
Sogawa
N
N
Furuta
H
H
Kamei
J
J
D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051381:Rats; D012737:Sex Factors; D013806:Theophylline / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*
D001993:Bronchodilator Agents; D013806:Theophylline