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Synthesis and detection of potential N-and α-C- oxidized metabolites of methadone and recipavrin

University of British Columbia

This t he si s describes the attempted characterization of a new metabolite of methadone which was observed by GCMS following β-glucuronidase hydrolysis of conjugated metabolites in the bile of methadone dosed rats. Kang (1) proposed a methylene nitrone structure for this metabolite and suggested that it arose from a glucuronide conjugated secondary hydroxylamine. The nitrone structure was also assigned to a chemical oxidation product of methadone's major metabolite EDDP which had identical GCMS characteristics to the metabolite (1). This thesis shows that the chemical oxidation product was in fact an oxaziridine which, under GC conditions, isomerizes to a formamide, with mass spectrum and retention time identical to the observed metabolite. Attempts to synthesize the potentially thermolabile methylene nitrone structure proposed by Kang failed due to instability of key intermediates or by facile isomerization to the formamide. A model compound, recipavrin, which lacks the ethyl ketone side chain of methadone, was selected to characterize potential N- and α-C-oxidized metabolites and to establish whether formation of the formamide-like metabolite was general to the many drugs containing the 4,4-diphenyl-N,N-dimethyl-2-butylamine structure. The nitrone, oxaziridine and formamide were synthesized as potential N-and α-C- oxidized metabolites of recipavrin and were characterized by GCMS, LCMS, NMR, IR and UV spectroscopy. By exact analogy to methadone, rats treated with recipavrin produced a conjugated metabolite, which upon β-glucuronidase hydrolysis had GCMS characteristics identical to that of the synthetic oxaziridine and formamide. LC and LCMS were not sensitive enough to determine whether the formamide or a thermolabile precursor was responsible for the observed metabolite. While it was not possible to determine which precursor was responsible for the formamide observed by GCMS, there is a good possibility that it is a formamide arising from a tertiary formamide carbinolamine glucuronide.

Text

2010-04-22

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http://hdl.handle.net/2429/24036

Pharmaceutical Sciences

University of British Columbia

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