Disposition of butanal oxime in rat following oral, intravenous and dermal administration

Abstract

1. The disposition of [1-¹⁴C]butanal oxime (BOX) was determined in the rat after oral, i.v. and dermal administration. 2. Oral doses of [¹⁴C]BOX (2 and 20 mg/kg) were predominantly excreted in the urine (> 42%) and converted to ¹⁴CO₂ (> 30%) and about 10% of the dose remained in the tissues 72 h post-dosing. 3. Eight and 16% of a 2 and 20 mg/kg dermal dose of BOX, respectively, were absorbed, due in part to rapid volatilization from the surface of the skin. 4. Oral doses of BOX were transformed into several polar and/or anionic metabolites that include sulphate conjugates and a significant amount of thiocyanate. 5. The effect of inhibitors on the metabolism of BOX was investigated using 1- aminobenzotriazole (ABT; an inhibitor of diverse cytochrome P450s) and trans-1,2- dichloroethylene (DCE; an inhibitor of CYP2E1). No thiocyanate anion was detected in the urine of rat treated with DCE or ABT. ABT markedly increased the production of ¹⁴CO₂ and excretion as volatile metabolites. DCE had no effect on ¹⁴CO₂ excretion, but increased exhalation of radiolabel. ABT also effectively blocked the expression of toxic effects attributable to cyanide in rat given near-lethal doses of BOX. 6. The data are consistent with two distinct pathways of metabolism for BOX, (1) reduction to an imine, hydrolysis and subsequent conversion of butyraldehyde to ¹⁴CO₂ and (2) CYP3A-catalysed dehydration of BOX to butyronitrile followed by CYP2E1- catalysed release of cyanide.