DISPOSITION OF BUTANAL OXIME IN RAT FOLLOWING ORAL, INTRAVENOUS AND DERMAL ADMINISTRATION

1. The disposition of [1-C-14]butanal oxime (BOX) was determined in th e rat after oral, i.v. and dermal administration. 2. Oral doses of [C- 14]BOX (2 and 20 mg/kg) were predominantly excreted in the urine (> 42 %) and converted to (CO2)-C-14 (> 30 %) and about 10 % of the dose re mained 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 B OX 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 P4 50s) 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 (CO2)-C-14 and excretio n as volatile metabolites. DCE had no effect on (CO2)-C-14 excretion, but increased exhalation of radiolabel. ABT also effectively blocked t he expression of toxic effects attributable to cyanide in rat given ne ar-lethal doses of BOX. 6. The data are consistent with two distinct p athways of metabolism for BOX, (1) reduction to an imine, hydrolysis a nd subsequent conversion of butyraldehyde to (CO2)-C-14 and (2) CYP3A- catalysed dehydration of BOX to butyronitrile followed by CYP2E1-catal ysed release of cyanide.