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Abstract
1. The fates of several intermediates of dibenz[b,f]-1,4-oxazepine (CR) metabolism in vivo and in vitro in rats have been examined to establish the metabolic and excretory sequence of CR.
2. The ring-opened 2-amino 2′-hydroxymethyldiphenyl ether (amino alcohol) added to isolated perfused rat liver was rapidly cleared in bile as a mixture of highly polar conjugates, whereas the major route of excretion in vivo was as the 4-, 7- and 9-hydroxylactam sulphates in urine.
3. The lactam of CR was eliminated exclusively in urine giving the same products as obtained for CR, but the distribution of metabolites of the C10-C11 dihydro derivative of CR was unlike that of the parent compound indicating that it occupies only a peripheral role in the fate of CR in vivo.
4. A mixture of 7-, 4- and 9-hydroxylactams derived from the enzymic hydrolysis of urinary sulphates was rapidly removed from blood, sulphated and secreted as sulphates into blood both in vivo and in isolated perfused liver. Little biliary excretion occurred.
5. When the urinary sulphates of the hydroxy lactams were administered i.v. to rats, 70% was eliminated in urine within 1 h; however, if the kidneys were ligated biliary excretion of sulphate was higher (58% in 5h).
6. After intraduodenal administration of the biliary conjugates of CR metabolism, all of the dose was resorbed to be re-secreted in bile or excreted as sulphates in urine.
7. These studies confirm that the major metabolic fate of CR in the rat is oxidation to lactam, followed by ring hydroxylation, sulphation and urinary excretion. However, a significant proportion of the dose is oxidized to the amino alcohol which is conjugated for biliary secretion, intestinal resorption and recycling.