Metabolism, pharmacokinetics, and excretion of the 5-hydroxytryptamine1b receptor antagonist elzasonan in humans.
The metabolism, pharmacokinetics, and excretion of a potent and selective 5-hydroxytryptamine(1B) receptor antagonist elzasonan have been studied in six healthy male human subjects after oral administration of a single 10-mg dose of [(14)C]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 t(1/2) 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 [(14)C]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.
Kamel
Amin
A
Departments of Pharmacokinetics, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, Connecticut, USA. amin.kamel@novartis.com
Obach
R Scott
RS
Colizza
Kevin
K
Wang
Weiwei
W
O'Connell
Thomas N
TN
Coelho
Richard V
RV
Kelley
Ryan M
RM
Schildknegt
Klaas
K
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D009025:Morpholines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D010879:Piperazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D053719:Tandem Mass Spectrometry
D009025:Morpholines; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D058829:Serotonin 5-HT1 Receptor Antagonists; C556408:elzasonan