Abstract
Purpose. We investigated the effect of acute renal failure on the neurotoxicity of cimetidine in rats.
Methods. Experimental acute renal failure was produced by bilateral ureteral ligation. Cimetidine was intravenously infused to ureter ligated (UL) and control rats, and cimetidine concentration in plasma, brain and cerebrospinal fluid (CSF) were compared.
Results. The cimetidine concentration in plasma was rapidly increased in UL rats as compared to control rats. The cimetidine concentration in CSF at the onset of convulsion did not depend on the infusion rate, suggesting that cimetidine in CSF equilibrates rapidly with the site of action for clonic convulsion. The cimetidine concentration in CSF of UL rats at the onset of clonic convulsion was lower than those of control rats.
Conclusions. Increased sensitivity to the drug on the central nervous system may contribute to increased toxicity of cimetidine with renal failure.
Similar content being viewed by others
REFERENCES
J. J. Schentag. Cimetidine-associated mental confusion: Further studies in 36 severely ill patients. Ther. Drug Monit., 2:133–142 (1980).
J. J. Schentag, F. B. Cerra, G. Calleri, E. DeGlopper, J. Q. Rose and H. Bernhard. Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet, 1:177–181 (1979).
M. E. Edmonds, R. F. U. Ashford, M. K. Brenner and A. Saunders. Cimetidine:dose neurotoxicity occur? Report of three cases. J. Roy. Soc. Med., 72:172–175 (1979).
B. J. Kimerblatt, F. B. Cerra, G. Calleri, M. J. Berg, M. A. Mcmillen and J. J. Schentag. Dose of serum concentration relationships in cimetidine-associated mental confusion. Gastroenterology, 78:791–795 (1980).
M. Shimokawa, K. Yamamoto, J. Kawakami, Y. Sawada and T. Iga. Effect of renal or hepatic dysfunction on neurotoxic convulsion induced by ranitidine in mice. Pharm. Res., 11:1519–1523 (1994).
M. Shimokawa, K. Yamamoto, Y. Sawada and T. Iga. Pharmacokinetic/pharmacodynamic evaluation of the risk of adverse reaction on central nervous system induced by H2 receptor antagonists: Hepatic and/or renal disease as risk factors. Xenobio. Metab. Dispos., 8:295–305 (1993)
M. Danhof, M. Hisaoka and G. Levy. Kinetics of drug action in disease states. II. Effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset of loss of righting reflex. J. Pharmacol. Exp. Ther., 230:627–631 (1984).
I. M. Ramzan and G. Levy. Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on pharmacodynamics of theophylline-induced seizures in rats. J. Pharmacol. Exp. Ther., 240:584–588 (1986).
I. M. Ramzan and G. Levy. Kinetics of drug action in disease states. XVI. Pharmacodynamics of theophylline-induced seizures in rats. J. Pharmacol. Exp. Ther., 236:708–713 (1986).
M. Danhof and G. Levy. Kinetics of Drug Action in Disease States. I. Effect of infusion rate on phenobarbital concentrations in serum, brain and cerebrospinal fluid of normal rats at onset of loss of righting reflex. J. Pharmacol. Exp. Ther., 229:44–50 (1983).
A. Hoffman and G. Levy. Kinetics of drug action in disease States. XXXIX. Effect of orally administered activated charcoal on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline administered intravenously to rats with renal failure. Pharm. Res., 7:242–246 (1990).
M. Hisaoka and G. Levy. Kinetics of drug action in disease states. XIII. Effect of dialyzable component(s) of uremic blood on phenobarbital concentrations in rats at onset of loss of righting reflex. J. Pharmacol. Exp. Ther., 234:180–183 (1985).
D. C. Taylor, P. R. Cresswell and D. C. Bartlett. The metabolism and elimination of cimetidine, a histamine H2-receptor antagonist, in the rat, dog, and man. Drug Metab. Dispos., 6:21–30 (1978).
Rights and permissions
About this article
Cite this article
Nakada, Y., Yamamoto, K., Kawakami, J. et al. Effect of Acute Renal Failure on Neurotoxicity of Cimetidine in Rats. Pharm Res 12, 1953–1957 (1995). https://doi.org/10.1023/A:1016200208174
Issue Date:
DOI: https://doi.org/10.1023/A:1016200208174