THEOPHYLLINE INHIBITS THE ELIMINATION OF FLUMAZENIL IN RABBITS

The effect of theophylline on the elimination of flumazenil during con stant infusion of 1 mg/kg per h over 240 min was investigated in 10 ra bbits. Theophylline was introduced as a single intravenous (i.v.) dose of 5 mg/kg (5 rabbits) and 15 mg/kg (5 rabbits), 100 min postinfusion . The addition of theophylline was associated with a new steady state which is approx. 32 and 46% higher for the 5 and 15 mg/kg doses, respe ctively. The elimination half-life of the drug was also increased from 18 and 12 min to about 28 and 42 min, respectively, for the two doses . Despite the relatively wide margin of safety for flumazenil the chan ges observed in plasma concentration during concomitant administration of theophylline may be clinically important. The pharmacokinetic para meters obtained prior to theophylline injection in the 10 rabbits were 406 ng/ml and 15 min for the steady state and elimination half-life, respectively. The variations between subjects in these parameters were as much as 2-fold. A simple and sensitive HPLC procedure to measure f lumazenil in plasma is also described.