Metabolism in Dogs of the Chloro- and Trifluoromethyl-Analogues of a Piperazine-substituted Dihydrobenzoxazepine

Abstract

1. The comparative metabolism of the ¹⁴C-labelled 7-chloro- and 7-tri-fluoromethyl-analogues of a piperazine-substituted dihydrobenzoxazepine (4-[3-(7-(chloro or trifluoromethyl)-5,11-dihydrobenz[b,e][1,4]-oxazepin-5-yl]-1-piperazine[14C2]ethanol, dihydrochloride), SQ 11,290 and SQ 11,005 respectively, has been studied in dogs.

2. After administration, both compounds were similarly excreted in urine and faeces or bile, and the radioactivity was similarly distributed in a variety of tissues. The highest concentrations of radioactivity were found in the lungs, liver, and the ocular layers consisting of the combined retina, choroid, and sclera. Similar blood levels were found for both compounds in dogs that had received equivalent doses of drug. An average of 5 or 8% of the dose was present as unchanged SQ 11,005 or SQ 11,290, respectively, in faeces, the predominant excretory route.

3. Two metabolites of each compound were isolated from bile. The major metabolite, a monooxygenated derivative of the tricyclic ring system, was present as the unconjugated compound in the faeces and as the glucuronide conjugate in the bile. The glucuronide conjugates of both parent compounds, were also excreted in the bile.

4. It is concluded that the chloro or trifluoromethyl substitution in the 7-position of the dibenzoxazepine ring system does not alter the biological disposition of these molecules in the dog.