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, 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 microCi/kg), no parent compound was detected in the blood; however, its debrominated metabolite, 2-methyleneglutaronitrile (2-MGN; Cmax 7.3 micrograms/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 14CO2. Although less than 5% of the dose was retained in tissues, approximately 12% was bound to the erythrocyte fraction of the blood. Following oral administration of [14C]BCB (80 mg/kg, 100 microgramsCi/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 micrograms/ml). Following topical application of [14C]BCB (25 mg/kg, 50 microgramsCi/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 as N-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 with N-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.
Sauer
J M
JM
Department of Pharmacology and Toxicology and the Center for Toxicology, The University of Arizona, Tucson 85721-0207, USA.
Smith
R L
RL
Bao
J
J
Kattnig
M J
MJ
Kuester
R K
RK
Sipes
I G
IG
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D008297:Male; D013058:Mass Spectrometry; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011310:Preservatives, Pharmaceutical / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344
D009570:Nitriles; D011310:Preservatives, Pharmaceutical; C039411:1,2-dibromo-2,4-dicyanobutane