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Clinical Chemistry 54: 1519-1527, 2008. First published July 17, 2008; 10.1373/clinchem.2008.105478
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(Clinical Chemistry. 2008;54:1519-1527.)
© 2008 American Association for Clinical Chemistry, Inc.

Drug Monitoring and Toxicology

Pitfalls and Prevention Strategies for Liquid Chromatography-Tandem Mass Spectrometry in the Selected Reaction– Monitoring Mode for Drug Analysis

François-Ludovic Sauvage1,3, Jean-Michel Gaulier1, Gérard Lachâtre1,2 and Pierre Marquet1,3,a

1 CHU Limoges, Department of Pharmacology-Toxicology, France; 2 Universite de Limoges, Faculty of Pharmacy, Laboratory of Toxicology, Limoges, France; 3 INSERM U850, Limoges, France.

aAddress correspondence to this author at: Department of Pharmacology-Toxicology, University Hospital, 2 av. Martin-Luther-King, 87042 LIMOGES cedex, France. Fax +33 555 05 61 62; e-mail pierre.marquet{at}unilim.fr.

Background: We observed cases of false-positive results with the use of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Different LC-MS/MS techniques that use the selected reaction-monitoring mode, routinely employed for the analysis and quantification of drugs and toxic compounds in biological matrices, were involved in the false-positive and potentially false-positive results obtained. We sought to analyze the causes of and solutions to this problem.

Methods: We used a previously reported LC-MS/MS general unknown screening method, as well as manual spectral investigation in 1 case, to perform verification and identification of interfering compounds.

Results: We observed that false-positive results involved: a metabolite of zolpidem that might have been mistaken for lysergic acid diethylamide, benzoylecgonine mistaken for atropine, and clomipramine and 3 phenothiazines that share several common ion transitions.

Conclusions: To prevent problems such as those we experienced, we recommend the use of stable-isotope internal standards when possible, relative retention times, 2 transitions or more per compound when possible, and acceptable relative abundance ratios between transitions, with an experience-based tolerance of ±15% for transitions with a relative abundance >10% and with an extension to ±25% for transitions <10% when the concentration is at the limit of quantification. A powerful general unknown screening procedure can help to confirm suspected interferences. Our results indicate that the specificity of screening procedures is questionable for LC-MS/MS analyses performed in the selected reaction-monitoring mode and involving a large number of compounds with only 1 transition per compound.






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Copyright © 2008 by the American Association for Clinical Chemistry.