The comparative metabolism of 2,6-dichlorothiobenzamide (Prefix) and 2,6-dichlorobenzonitrile in the dog and rat

Abstract

A single oral dose of either [C14]Prefix or 2,6-dichlorobenzo[C14]nitrile to rats is almost entirely eliminated in 4 days: 84.8-100.5% of C14 from [C14]Prefix is excreted, 67.3-79 J% in the urine, and 85.8-97.2% of C14 from 2,6-dichlorobenzo-[C14]nitrile is excreted, 72.3-80.7% in the urine. Only 0.37[plus or minus]0.03% of the dose of [C14]Prefix and 0.25[plus or minus]0.03% of the dose of 2,6-dichloro-benzo[C14]nitrile are present in the carcass plus viscera after removal of the gut. Rats do not show sex differences in the pattern of elimination of the respective metabolites of the 2 herbicides. The rates of elimination of C14 from the 2 compounds in the 24 hr. and 48 hr. urines are not significantly different (P > 0.05) from one another. 2. After oral administration to dogs, 85.9-106.1% of C14 from [Ci4]prefix is excreted. 66.6-80.9% in the urine, and 86.8-92.5% of C14 from 2,6-dichlorobenzo[C14]nitrile is excreted, 60.0-70.1% in the urine. Dogs do not show sex differences in the pattern of eliminating the metabolites of either Prefix or 2,6-dichlorobenzonitrile. Dogs and rats do not show species differences in the patterns of elimination of the 2 herbicides. Prefix and 2,6-dichlorobenzonitrile are completely metabolized; unchanged Prefix and 2,6-dichlorobenzonitrile are absent from the urine and feces, and from the carcasses when elimination is complete. In the hydrolysed urine of rats dosed with either [C14]Prefix or 2,6-dichlorobenzo[C14]nitrile. 2,6-dichloro-3-hydroxybenzonitrile accounts for approx. 42% of the C14, a further 10-11% is accounted for by 2,6-dichlorobenzamide, 2,6-dichlorobenzolc acid, 2,6-dichloro-3-and -4-hydroxybenzoic acid and 2,6-dichloro-4-hydroxybenzonltrile collectively, and 25-30% by 6 polar constituents, of which 2 are sulfur-containing amino acids. In the unhydrolysed urines of rats dosed with either [C14]Prefix or 2,6-dichlorobenzo[C14]nitrile, there are present free 2,6-dichloro-3-and-4-hydroxybenzonitrile, their glucuronide conjugates, ester glucuronides of the principal aromatic acids that are present in the hydrolysed urines, and 2 sulphur-containing metabolites analogous to mercapturic acids or premercapturic acids. Prefix is this extensively transformed into 2,6-dichlorobenzonitrile: R.CS.NH2 [forward arrow]R.CN + H2S, where R=C6H3Cl2. However, the competitive reaction: R.CS.NH2 H2O[forward arrow]R.CO.NH2 + H2S takes place to a very limited extent.