UBC Theses and Dissertations

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UBC Theses and Dissertations

Studies on the metabolism of tocainide in humans Kwok, David W. K.


Tocainide carbamoyl ester glucuronlde (TOCG) (R-NHCO.O-GA) is a major metabolite of tocainide (TonocardR). The structure of TOCG was first proposed by Elvin (35) based on the structure of 3-(2,6-xylyl)-5-methylhydantoln, a base hydrolyzed product of TOCG in urine. Due to the presence of two carbonyl groups on the hydantoin ring, TOCG was proposed to arrive from a novel metabolic pathway involving the addition of carbon dioxide to the terminal nitrogen of tocainlde followed by glucuronic acid conjugation. With the initial intention of carrying out a bioavailability study of tocainide using a deuterated pseudoracemic sample, the stereospecific synthesis of R(-)- and S(+)-trideuterated tocainide was attempted through two synthetic approaches. This thesis describes a chemical reaction between tocainide and urea, a second pathway which leads to the formation of 3-(2,6-xylyl)-5-methylhydantoin through a tocainide ureide intermediate. With this observation, a tocainide N-ureide glucuronide structure (R-NHCO.NH-GA) was proposed for TOCG in support of the theory that an in vivo reaction between tocainide and urea may have resulted a tocainide N-ureide which can be further conjugated with glucuronic acid. Attempts were made to assign the correct structure of TOCG by identification of the theoretical tocainide carbamic acid (based on Elvln's proposed structure) or the tocainide N-ureide intermediate in urine. This thesis also describes the preparative HPLC isolation and the structural characterization of this novel glucuronic acid conjugate. Evidence obtained as proof for the identity of TOCG as a conjugate was obtained from acid hydrolysis, basic hydrolysis, beta-glucuronidase hydrolysis, with or without the presence of sacchro-1,4-lactone, and a naphthoresorcinol color test. Structural evidence for the carbamoyl ester linkage of TOCG was obtained from proton-NMR and FAB analysis. The 400-MHz proton NMR data of the isolated glucuronide provided partial evidence for the intact structure of TOCG. In FAB analysis, the [M+1] ion adduct at m/z 413, [M+Na] at m/z 435, and [M-H+2Na] at m/z 457 have provided positive evidence for the molecular ion of TOCG at m/z 412 in favor of the carbamoyl ester structure. In addition to the hydrolysis of TOCG at pH > 12 to the hydantoin, this hydantoin was found to also undergo spontaneous first-order hydrolysis at pH > 12. To assay the levels of TOCG in urine as the hydantoin, a set of accurately timed calibration samples were employed in an assay protocol to take Into account the spontaneous hydrolysis of the hydantoin. Based on this analytical approach, the levels of TOCG were determined in three subjects both after an IV and oral dose of 200 mg tocainide HC1. The urinary excretion half-lives of TOCG of 13.86 hours and 13.33 hours, after an IV and oral dose respectively, were found to agree with literature values.

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