Acute and sub-acute oral safety profile of fumarate in normotensive Wistar rats

Abstract

Fumarate, the tricarboxylic acid cycle metabolite, has been documented to exert an antihypertensive effect. However, there is no report on its oral safety profile. This study assessed the effect of acute and sub-acute dosing of fumarate in normotensive animals. Acute toxicity test was done using Lorke’s method. Sub-acute testing involved the treatment of Wistar rats with 50, 150, and 500 mg/kg of fumarate for 28 days. Blood samples were collected after 28 days for haematological and biochemical analyses. Histological analyses were carried out on the heart, kidney, liver, and aorta. No mortality/physical toxicity was observed in both acute and sub-acute tests. In fumarate-treated female rats, liver weight decreased by 24 %, while heart weight increased by 33 % at 500 mg/kg, p<0.01. Red cell indices did not significantly change from control (p>0.05). White cell, monocyte, and lymphocyte levels were increased (p<0.05). There were no changes in body weights in fumarate-treated rats. Triglyceride levels were decreased at 50 mg/kg in fumarate-treated male rats only (p<0.01). There was a dose-dependent increase in ALT levels in male-treated fumarate rats (p<0.05). Aside from the mild steatosis in the liver, histological sections of the heart, kidney, and aorta did not reveal any gross malformations. The result of this study demonstrates that fumarate is relatively non-toxic and safe in acute and subacute usage.