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 v ivo toxicity and plasma concentration of theophylline. Theophylline was adm inistered intravenously in single doses (50, 100, 150 and 200 mg kg(-1) onc e a day) or repeated doses (12.5, 25 and 90 mg kg(-1)/day for 28 days) in r ats. Plasma concentrations of theophylline increased dose-dependently in bo th 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) no r repeated dose at 12.5 mg kg(-1)/day injections of theophylline showed tox ic signs, in which plasma concentrations of theophylline were less than 110 and 22.5 mug ml(-1), respectively. Theophylline induced myocardial fibrosi s in 25 mg kg(-1)/day and more treated groups: in which plasma concentratio ns of theophylline were more than 50 mug 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 mug ml(-1) in single 100 mg kg(-1) and 162 mug 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 mug ml(-1). Moreover, the recovery period from signs of toxic pois oning 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 t he in vivo toxicity of theophylline is highly dependent on plasma concentra tions in rats which received single and also repeated doses of theophylline . (C) 2001 Academic Press.