Formation of cyanide after i. v. administration of the oxime HI 6 to dogs

Abstract

HI6(pyridinium, 1-[[[4-(aminocarbonyl)pyridinio] methoxy]methyl]-2-[(hydroxyimino)methyl]-dichloride belongs to a series of bisquaternary pyridinium oximes that are effective against poisoning with extremely toxic organophosphates. Since HI6 has been shown to be unstable at pH 7.4 and to release significant amounts of cyanide, a study was undertaken to determine the degree of cyanide formation from HI 6 in vivo. When HI 6 (100 μmol/kg) was administered i. v. to dogs, the animals showed no signs of cyanide toxicity but exhibited some cholinomimetic symptoms, including retching, hypersalivation and enhanced intestinal motility. Cyanide content in whole blood was monitored after production of methemoglobinemia (30%) by 4-dimethylaminophenol in order to sequester cyanide within red cells. Maximal cyanide contents of 20 μmol/l were found in blood after 90 min. Calculation of the area under the concentration versus time curve for blood cyanide indicates that about 4% of HI 6 produced cyanide. Determination of the pharmacokinetic parameters of HI 6 (V_D=0.31 l/kg; k_el=0.76 h⁻¹) and of cyanide (V_D=0.086 l/kg; k_el=0.52 h⁻¹) together with the apparent first order rate constant of cyanide formation from HI 6 in vitro (0.174 h⁻¹, pH 7.4, 37°) allowed the simulation of a cyanide concentration curve that fitted with the experimental data points, indicating that cyanide formation in vivo was not bio-catalyzed. It is concluded that cyanide formation from HI 6 may not be regarded as a potential hazard, since cyanide elimination exceeded markedly its formation. Whether this conclusion also holds true for man has to be established.