Abstract
The metabolism, pharmacokinetics, and excretion of a potent and selective 5-hydroxytryptamine1B receptor antagonist elzasonan have been studied in six healthy male human subjects after oral administration of a single 10-mg dose of [14C]elzasonan. Total recovery of the administered dose was 79% with approximately 58 and 21% of the administered radioactive dose excreted in feces and urine, respectively. The average t1/2 for elzasonan was 31.5 h. Elzasonan was extensively metabolized, and excreta and plasma were analyzed using mass spectrometry and NMR spectroscopy to elucidate the structures of metabolites. The major component of drug-related material in the excreta was in the feces and was identified as 5-hydroxyelzasonan (M3), which accounted for approximately 34% of the administered dose. The major human circulating metabolite was identified as the novel cyclized indole metabolite (M6) and accounted for ∼65% of the total radioactivity. A mechanism for the formation of M6 is proposed. Furthermore, metabolism-dependent covalent binding of drug-related material was observed upon incubation of [14C]elzasonan with liver microsomes, and data suggest that an indole iminium ion is involved. Overall, the major metabolic pathways of elzasonan were due to aromatic hydroxylation(s) of the benzylidene moiety, N-oxidation at the piperazine ring, N-demethylation, indirect glucuronidation, and oxidation, ring closure, and subsequent rearrangement to form M6.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034595.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- 5-HT
- 5-hydroxytryptamine, serotonin
- CP-448,187
- 4-(3,4-dichloro-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzylidene]-thiomorpholin-3-one, elzasonan
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- CID
- collision-induced dissociation
- HPLC
- high-pressure liquid chromatography
- r
- recombinant
- CE-244,600
- [4-(3,4-dichloro-phenyl)-2-[5-hydroxy-2-(4-methyl-piperazin-1-yl)-benzylidene]-thiomorpholin-3-one]
- CP-609,707
- elzasonan N-oxide
- CP-459,326
- N-desmethylelzasonan
- AUC
- area under the plasma concentration-time curve
- ARC
- accurate radioactivity counting
- P450
- cytochrome P450.
- Received May 19, 2010.
- Accepted July 28, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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