RT Journal Article
SR Electronic
T1 Metabolic and Dispositional Fate of 1,2-Dibromo-2,4-Dicyanobutane in the Male Fischer 344 Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 429
OP 436
VO 26
IS 5
A1 John-Michael Sauer
A1 Richard L. Smith
A1 JingQi Bao
A1 Margaret J. Kattnig
A1 Robert K. Kuester
A1 I. Glenn Sipes
YR 1998
UL http://dmd.aspetjournals.org/content/26/5/429.abstract
AB Studies were conducted to characterize the absorption, disposition, metabolism, and excretion of 1,2-dibromo-2,4-dicyanobutane (BCB; methyldibromoglutaronitrile) following iv, oral, and topical administration to male Fischer 344 rats. Following iv administration of [14C]BCB (8 mg/kg, 120 μCi/kg), no parent compound was detected in the blood; however, its debrominated metabolite, 2-methyleneglutaronitrile (2-MGN; Cmax 7.3 μg/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 as14CO2. Although less than 5% of the dose was retained in tissues, ∼12% was bound to the erythrocyte fraction of the blood. Following oral administration of [14C]BCB (80 mg/kg, 100 μCi/kg), approximately 85% of the dose was absorbed, whereas 72% of the dosed radioactivity was recovered in the urine and 9.7% in the feces, 7.5% was exhaled as 14CO2, 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 (Cmax 0.32 μg/ml). Following topical application of [14C]BCB (25 mg/kg, 50 μCi/kg), less than 12% of the dose was absorbed, with the major route of excretion being the urine (6.6% of dose). Urinary metabolite profiles were nearly identical for each route of administration, and the primary urinary metabolite was a mercapturate conjugate of 2-MGN that was identified asN-acetyl-S-(2,4-dicyanobutane)-l-cysteine. BCB was found to be extremely labile in whole blood, plasma, and glutathione containing solutions, and in each case the formation of 2-MGN could be reduced by the alkylation of free-sulfhydryls withN-ethylmaleimide. These results suggest that BCB is totally debrominated prior to systemic distribution, and tissue exposure to intact BCB seems to be exceedingly low regardless of route of administration. The American Society for Pharmacology and Experimental Therapeutics