General unknown screening procedure for the characterization of human drug metabolites: Application to loratadine phase I metabolism.
This article describes the application of a recently developed general unknown screening (GUS) strategy based on LC coupled to a hybrid linear IT-triple quadrupole mass spectrometer (LC-MS/MS-LIT) for the simultaneous detection and identification of drug metabolites following in vitro incubation with human liver microsomes. The histamine H1 receptor antagonist loratadine was chosen as a model compound to demonstrate the interest of such approach, because of its previously described complex and extensive metabolism. Detection and mass spectral characterization were based on data-dependent acquisition, switching between a survey scan acquired in the ion-trapping Q3 scan mode with dynamic subtraction of background noise, and a dependent scan in the ion-trapping product ion scan mode of automatically selected parent ions. In addition, the MS(3) mode was used in a second step to confirm the structure of a few fragment ions. The sensitivity of the ion-trapping modes combined with the selectivity of the triple quadrupole modes allowed, with only one injection, the detection and identification of 17 phase I metabolites of loratadine. The GUS procedure used in this study may be applicable as a generic technique for the characterization of drug metabolites after in vitro incubation, as well as probably in vivo experiments.
Picard
Nicolas
N
Inserm, UMR-S850, Limoges Cedex, France.
Dridi
Dorra
D
Sauvage
François-Ludovic
FL
Boughattas
Naceur A
NA
Marquet
Pierre
P
D000818:Animals; D002853:Chromatography, Liquid / Q000295:instrumentation / Q000379:methods; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D017336:Loratadine / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000295:instrumentation / Q000379:methods; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D039563:Histamine H1 Antagonists, Non-Sedating; D004364:Pharmaceutical Preparations; D017336:Loratadine