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

The fate of dibenz[b,f]-1,4-[11(14)-C]oxazepine (CR) in rats, rhesus monkey and guinea-pig and in isolated perfused rat livers has been examined. 14C-CR was administered to rats at doses from 1.56 to 3470 mumol/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. 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. 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. 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. Whole-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.

The metabolism of dibenz[b,f]-1,4-oxazepine (CR): in vivo hydroxylation of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one and the NIH shift.

Studies of the in vivo metabolism of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one (2) specifically deuteriated at C7 implicate an arene oxide intermediate during the conversion to 7-hydroxy-2 (4) as evidenced by the observation of the NIH shift.

The biological importance of organophosphorus compounds containing a carbon-phosphorus bond.

Organophosphorus anticholinesterase compounds may be derivatives of phosphoric acid or of a phosphonic acid. The phosphonic acid derivatives are usually more reactive and more toxic than the phosphoric acid derivatives. Examples are given to show that differences in the chemical and biological reactivity of phosphates and phosphonates reflect many different aspects of their chemical structure. Some recently discovered naturally-occurring phosphonates are described, together with some synthetic phosphonate analogues of naturally-occurring phosphates. The utility of these synthetic phosphonates as tools for probing enzymic reaction sequences is discussed.

Dehydrogenation of the phosphonate analogue of glucose 6-phosphate by glucose 6-phosphate dehydrogenase.

6,7 -Dideoxy-alpha-D-gluco-heptose 7-phosphonic acid, the isosteric phosphonate analogue of glucose 6-phosphate, was synthesized in six steps from the readily available precursor benzyl 4,6-O-benzylidene-alpha-D-glucopyranoside. The analogue is a substrate for yeast glucose 6-phosphate dehydrogenase, showing Michaelis-Menten kinetics at pH7.5 and 8.0. At both pH values the Km values of the analogue are 4-5 fold higher and the values approx. 50% lower than those of the natural substrate. The product of enzymic dehydrogenation of the phosphonate analogue at pH8.5 is itself a substrate for gluconate 6-phosphate dehydrogenase.