Disposition of butanal oxime in rat following oral, intravenous and dermal administration.
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.
Mathews
J M
JM
Center for Bioorganic Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Black
S R
SR
Burka
L T
LT
D000042:Absorption; D000279:Administration, Cutaneous; D000284:Administration, Oral; D000447:Aldehydes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D010091:Oximes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D000447:Aldehydes; D002250:Carbon Radioisotopes; D010091:Oximes; C018475:butyraldehyde