An Automated Method for the Determination of Trimebutine and N-Mono-Desmethyl Trimebutine by On-Line Turbulent Flow Coupled with Liquid Chromatography-Tandem Mass Spectrometry in Human Plasma: Application to a Fatal Poisoning Case with Toxicokinetic Study.
A liquid chromatography-MS-MS turbulent flow on-line extraction method was developed for the determination of trimebutine (TMB) and its main active metabolite N-mono-desmethyltrimebutine (nortrimebutine or nor-TMB) in human plasma. After protein precipitation and internal standard (IS, haloperidol-d4) addition, 50 µL of the supernatant were transferred onto a Cyclone-Turbo-Flow extraction column followed by an Hypersil PFP Gold analytical column. Detection was carried out on a triple quadrupole tandem mass spectrometer using positive electrospray ionization. The transitions used were m/z 388.0→343.0, 374.0→195.0 and 380.1→169.0 for TMB, nor-TMB and IS, respectively. The method was validated over the concentration range of 10-1,000 ng/mL for both compounds. The accuracy evaluated at three concentrations was within 90.0-98.5% and the intra- and interday coefficient of variation's for the two molecules were <8.7%. The method was applied to a toxicokinetic study of a self-poisoning case with TMB in a 19-old girl. The concentration of TMB decreased from 747 to 77 ng/mL, while nor-TMB decreased from 9,745 to 205 ng/mL after 5 days and the fatal issue. This case confirms the literature underlining the potential toxicity of TMB, which has long time been considered as a harmless molecule.
Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches et Université Versailles Saint-Quentin, 104 Boulevard R. Poincaré, Saint-Quentin 92380, France.
Islam Amine
IA
Larabi
Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches et Université Versailles Saint-Quentin, 104 Boulevard R. Poincaré, Saint-Quentin 92380, France.
Charlotte
C
Duverneuil-Mayer
Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches et Université Versailles Saint-Quentin, 104 Boulevard R. Poincaré, Saint-Quentin 92380, France.
Emuri
E
Abe
Service de réanimation, Centre Hospitalier Universitaire Necker-Enfants malades, AP-HP, Paris et Université Paris Descartes, 149 Rue de Sèvres, Paris 75015, France.
Frédéric
F
Baud
Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches et Université Versailles Saint-Quentin, 104 Boulevard R. Poincaré, Saint-Quentin 92380, France jean-claude.alvarez@rpc.aphp.fr.
Jean-Claude
JC
Alvarez
D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D057230:Limit of Detection; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D066007:Toxicokinetics; D014287:Trimebutine / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics* / Q000506:poisoning*; D055815:Young Adult
C053065:N-desmethyltrimebutine; D014287:Trimebutine