The characterisation of the major metabolite of salmeterol in the dog

Salmeterol xinafoate is the first of a new class of long acting, selective beta(2)-adrenoceptor agonists introduced for the treatment of asthma [1,2]. The major metabolite of salmeterol in the dog has been identified as the 3 -catechol sulphate of the benzoic acid derivative. This metabolite was isol ated from dog bile and was shown to have very similar physiochemical proper ties to a major endogenous component of bile, the bile acids, creating a co mplex analytical challenge. Initial experiments, involving hydrolysis with the enzyme sulphatase, suggested that the metabolite was a sulphate conjuga te. However, complete identification of the metabolite was complicated in p art due to the loss, by metabolism, of deuterium atoms added to the compoun d, specifically as a marker for mass spectrometry. Subsequently, a synthesi s of salmeterol was completed with deuterium labels in different positions. This material was used as a substrate for dog liver slices, a simpler matr ix than dog bile, which provided the basis for the metabolite's identificat ion. The metabolite was characterised by the use of spectroscopic technique s, in particular LC/MS, LC/MS/MS and NMR. (C) 1998 Elsevier Science B.V. Ai l rights reserved.