METABOLIC AND DISPOSITIONAL FATE OF 1,2-DIBROMO-2,4-DICYANOBUTANE IN THE MALE FISCHER-344 RAT

Studies were conducted to characterize the absorption, disposition, me tabolism, and excretion of 1,2-dibromo-2,4-dicyanobutane (BCB; methyld ibromoglutaronitrile) following iv, oral, and topical administration t o male Fischer 344 rats. Following iv administration of [C-14]BCB (8 m g/kg, 120 mu Ci/kg), no parent compound was detected in the blood; how ever, its debrominated metabolite, 2-methyleneglutaronitrile (2-MGN; C -max 7.3 mu g/ml), was observed up to 1 hr, Within 72 hr, greater than 60% of the dose was excreted in the urine and 4.1% in the feces, and 6.6% was exhaled as (CO2)-C-14. Although less than 5% of the dose was retained in tissues, similar to 12% was bound to the erythrocyte fract ion of the blood, Following oral administration of [C-14]BCB (80 mg/kg , 100 mu Ci/kg), approximately 85% of the dose was absorbed, whereas 7 2% of the dosed radioactivity was recovered in the urine and 9.7% in t he feces, 7.5% was exhaled as (CO2)-C-14, 3.5% bound to tissues, and 2 .6% bound to blood, Although parent compound could not be detected in the blood following oral administration, 2-MGN was detected (C-max 0.3 2 mu g/ml), Following topical application of [C-14]BCB (25 mg/kg, 50 m u Ci/kg), less than 12% of the dose was absorbed, with the major route of excretion being the urine (6.6% of dose), Urinary metabolite profi les were nearly identical for each route of administration, and the pr imary urinary metabolite was a mercapturate conjugate of 2-MGN that wa s identified as N-acetyl-S-(2,4-dicyanobutane)-L-cysteine. BCB was fou nd to be extremely labile in whole blood, plasma, and glutathione cont aining solutions, and in each case the formation of 2-MGN could be red uced by the alkylation of free-sulfhydryls with N-ethylmaleimide. Thes e results suggest that BCB is totally debrominated prior to systemic d istribution, and tissue exposure to intact BCB seems to be exceedingly low regardless of route of administration.