An Automated Method for the Determination of Trimebutine andN-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

Abstract

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.

Simultaneous Determination of Ruscogenin, Neoruscogenin, Trimebutin, and Parabens in Cream Formulation by Reverse Phase High Performance Liquid Chromatography

“…None of these methods were developed for the analysis of RUS from pharmaceutical preparations. Reported methods for the determination of TB of from different matrices include HPLC [26][27][28][29][30][31][32][33], LC-MS/MS [34][35][36], spectrophotometric [28, [37][38][39][40][41], and electrochemical [42][43][44][45][46][47][48]. There was only one method developed and validated for TB determination from the pharmaceutical formulations [42].…”