Effect of renal or hepatic dysfunction on neurotoxic convulsion induced by ranitidine in mice.
We investigated the effect of acute renal and hepatic dysfunction on the neurotoxicity of ranitidine, a histamine H2 receptor antagonist. Experimental acute hepatic and renal dysfunction in mice were produced by i.p. injection of uranyl nitrate (UN) and carbon tetrachloride (CT), respectively. Ranitidine was then constantly infused into the tail vein until the onset of clonic convulsion. When compared to control mice, UN treated mice had a significantly shorter onset time to clonic convulsion, lower total dose and higher plasma concentration at initiation of clonic convulsion. In contrast, the convulsive threshold concentration in the brain of UN treated mice was not significantly different from that of control mice. In CT treated mice, all pharmacokinetic and pharmacodynamic data described above were not significantly different from those of the control mice. No significant difference in the brain/plasma concentration ratio was observed between both disease models and the corresponding control mice. Finally, the effect of UN and CT treatment on the convulsive potency after intracerebral (i.c.) administration of ranitidine was investigated in mice. Potentiation of the intrinsic neurotoxic sensitivity to ranitidine could not be demonstrated for mice with renal or hepatic dysfunction. From these findings, we conclude that renal dysfunction is a risk factor for ranitidine neurotoxicity, and this increased risk results from increase in the drug concentration in plasma and brain as a result of impaired renal excretion. No apparent effect of acute hepatic dysfunction was observed on both the pharmacokinetic and pharmacodynamic behavior of the drug.
Shimokawa
M
M
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Yamamoto
K
K
Kawakami
J
J
Sawada
Y
Y
Iga
T
T
D000208:Acute Disease; D000818:Animals; D007674:Kidney Diseases / Q000503:physiopathology*; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011899:Ranitidine / Q000493:pharmacokinetics / Q000633:toxicity*; D012307:Risk Factors; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism
D011899:Ranitidine