Exogenous methemoglobin as a cyanide antidote in rats

Abstract

The effects of the administration of methemoglobin (MetHb) prepared in vitro were evaluated in Sprague-Dawley rats given increasing doses of potassium cyanide (KCN). Median lethal dose (LD50) studies were conducted by giving intraperitoneal injections of KCN (in 0.3- to 0.5-ml volumes), then 2 min later administering intravenous (iv) doses of 1000, 1500, or 2500 mg/kg of MetHb through the tail vein. Control rats received an equivalent volume of saline. The resulting LD50 values for KCN were 7.4 +/- 1.1, 11.7 +/- 1.1, 13.9 +/- 1.0, and 14.2 +/- 1.0 mg/kg (mean +/- SD) for the control (no MetHb) and 1000-, 1500-, and 2500-mg/kg dose groups, respectively. Additional groups of rats were given 1000, 1500, or 2500 mg/kg MetHb and submitted for necropsy. The gross finding of darkened kidneys was present in both dose groups, but became consistent and more prominent in the 2500-mg/kg dose group. Evidence of pathologic changes was not present in other organs. Single-dose pharmacokinetic studies were conducted using iv doses of 1600 and 2500 mg/kg MetHb. The elimination half-life was similar in both doses (62.6 min), but the volume of distribution (95.3 +/- 7.2 and 126.3 +/- 5.2 ml/kg, mean +/- SE) and clearance (1.1 +/- 0.1 and 1.5 +/- 0.1 ml/min/kg) were significantly different (P less than 0.05) for the 1600- and 2500-mg/kg dose groups, respectively. From these data we conclude that although MetHb is cleared from the vascular system rapidly, it may be an effective and nontoxic antidote for doses of cyanide up to twice that of the control LD50.