The characterisation of the major metabolite of salmeterol in the dog.
Salmeterol xinafoate is the first of a new class of long acting, selective beta2-adrenoceptor agonists introduced for the treatment of asthma. The major metabolite of salmeterol in the dog has been identified as the 3-catechol sulphate of the benzoic acid derivative. This metabolite was isolated from dog bile and was shown to have very similar physiochemical properties to a major endogenous component of bile, the bile acids, creating a complex analytical challenge. Initial experiments, involving hydrolysis with the enzyme sulphatase, suggested that the metabolite was a sulphate conjugate. However, complete identification of the metabolite was complicated in part due to the loss, by metabolism, of deuterium atoms added to the compound, specifically as a marker for mass spectrometry. Subsequently, a synthesis of salmeterol was completed with deuterium labels in different positions. This material was used as a substrate for dog liver slices, a simpler matrix than dog bile, which provided the basis for the metabolite's identification. The metabolite was characterised by the use of spectroscopic techniques, in particular LC/MS, LC/MS/MS and NMR.
Bowers
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Glaxo Wellcome Inc., RTP, NC 27709, USA. gdb4925@glaxowellcome.com
Bayliss
M K
MK
Donnelly
M C
MC
Fellows
I
I
Ismail
I M
IM
Mookherjee
C R
CR
D000420:Albuterol / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000737:chemistry*; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D000068299:Salmeterol Xinafoate; D013431:Sulfates / Q000378:metabolism*
D013431:Sulfates; D000068299:Salmeterol Xinafoate; D000420:Albuterol