Kinetics of drug action in disease states. XIX. Effect of experimental liver disease on the neurotoxicity of theophylline in rats.

There are pronounced interindividual differences in the neurotoxicity of theophylline in humans as reflected by the wide range of plasma theophylline concentrations associated with the occurrence of life-threatening, generalized seizures in patients treated with this widely used bronchodilator. The variability indicates that there may be a number of as yet unrecognized risk factors for theophylline neurotoxicity. After the development of an animal model of theophylline-induced seizures, renal failure was identified as one such risk factor. This investigation was designed to determine if experimental liver disease will alter the neurotoxic effect of theophylline. Studies were performed on rats with extrahepatic cholestasis produced by bile duct ligation and with hepatic necrosis induced by carbon tetrachloride administration and on respective controls. Theophylline was infused i.v. at 1.03 mg/min until the onset of maximal seizures. Theophylline and theophylline metabolite concentrations at that time were determined in serum (unbound and total drug), brain and cerebrospinal fluid. Extrahepatic cholestasis was associated with small increases in unbound theophylline concentration in serum, theophylline concentration in brain and serum free fraction in serum at onset of seizures. The concentrations of theophylline metabolites were negligible. There were no apparent effects of extrahepatic cholestasis or hepatic necrosis on theophylline concentrations at onset of seizures in cerebrospinal fluid, the fluid that was shown in a preceding study to be the best indicator of the theophylline concentration at the site of the neurotoxic effect. It is concluded that experimental liver disease had no apparent effect on the neurotoxicity of theophylline under the conditions of this investigation.