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 t he neurotoxicity of ranitidine, a histamine H-2 receptor antagonist. E xperimental 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 v ein until the onset of clonic convulsion. When compared to control mic e, UN treated mice had a significantly shorter onset time to clonic co nvulsion, lower total dose and higher plasma concentration at initiati on of clonic convulsion. In contrast, the convulsive threshold concent ration in the brain of UN treated mice was not significantly different from that of control mice. In CT treated mice, all pharmacokinetic an d pharmacodynamic data described above were not significantly differen t from those of the control mice. No significant difference in the bra in/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.) adminis tration of ranitidine was investigated in mice. Potentiation of the in trinsic neurotoxic sensitivity to ranitidine could not be demonstrated for mice with renal or hepatic dysfunction. From these findings, we c onclude that renal dysfunction is a risk factor for ranitidine neuroto xicity, and this increased risk results from increase in the drug conc entration 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.