The fate of dibenz[b,f]-1,4-oxazepine (CR) in the rat, rhesus monkey and guinea-pig. Part I. Metabolism in vivo

Abstract

1. The fate of dibenz[b,f]-1,4-[11¹⁴-C]oxazepine (CR) in rats, rhesus monkey and guinea-pig and in isolated perfused rat livers has been examined.

2. ¹⁴C-CR was administered to rats at doses from 1.56 to 3470 μmol/kg and irrespective of dose or route of administration most (59–93%) was eliminated in the urine as primarily the sulphates of the 7-, 4- and 9-hydroxylated 10,11-dihydrodibenz[b,f]-1,4-oxazepine-11(10H)-one.

3. In blood, both in vivo and in liver perfusates, CR concentrations decreased biphasically to be replaced initially with CR-lactam (dihydrodibenz[b,f]-1,4-oxazepine-11(10H)-one), followed by the sulphates of the 7-, 4- and 9-hydroxylactams. The rate of disappearance of CR in liver perfusates was slower than in vivo.

4. Bile contained only small amounts of sulphate conjugates and significant amounts of conjugated 2-amino-2′-hydroxymethyldiphenyl ether (amino alcohol). This was not identified in the urine or blood of rats.

5. Preliminary studies in rhesus monkey and the guinea-pig show similar excretory patterns and metabolites. However, only free hydroxylactams were isolated from monkey urine and traces of the amino alcohol were detected in guinea-pig urine.

6. ühole-body autoradiography of mice confirm the rapid disappearance of CR from blood into heart, liver, kidneys and small intestine with evidence of biliary excretion. It is consistent with the rat studies showing the rapid absorption of a highly lipophilic compound undergoing hepatic metabolism, biliary secretion, enterohepatic recirculation and renal excretion.