CYCLOSPORINE ENHANCES THEOPHYLLINE NEUROTOXICITY IN RATS

Treatment with cyclosporine may be associated with adverse central ner vous system (CNS) effects as well as with the potentiation of effects of certain other drugs. In particular, theophylline-induced seizures, which are often fatal and occur unpredictably over a wide range of ser um theophylline concentrations, may be precipitated. To study this int eraction, adult rats that were injected with cyclosporine or placebo ( 50 mg/kg in a single dose or on each of four consecutive days) receive d a constant infusion of theophylline (2 mg/min iv) until the onset of maximal seizures. At that time, blood, cerebrospinal fluid (CSF), and brain tissue samples were obtained for theophylline concentration det erminations by HPLC, as well as for measurement of several biochemical parameters in the serum. Consecutive cyclosporine administration (but not a single dose) reduced serum protein levels. There was a small in crease in theophylline sensitivity after a single dose of cyclosporine . The CSF theophylline concentrations at the onset of seizures were 21 5 +/- 10 vs 202 +/- 5 mg/L (P < 0.04); however, sequential cyclosporin e treatment resulted in significant lowering of the CSF theophylline c oncentrations required to prodcue convulsions (231 +/- 8 vs 191 +/- 10 , P < 0.001). Likewise, the drug concentrations at the onset of convul sions in both the brain and serum were significantly lower in cyclospo rine-treated rats than in control animals. Thus, cyclosporine treatmen t may be a predisposing factor for theophylline toxicity and increase the risk for generalized seizures.