Lomerizine, trimetazidine and bis-(4-fluorophenyl)-methylpiperazine in human urine after oral administration of lomerizine dihydrochloride: analysis by liquid chromatography-high resolution-tandem mass spectrometry.

Abstract

In sports drugs testing, the differentiation between the abuse of the prohibited substance trimetazidine and that of the permitted drug lomerizine is required because trimetazidine is one of the metabolites of lomerizine. Therefore, it is important to identify a lomerizine-specific metabolite in urine that allows making the distinction. In this study, a simple dilute-and-shoot method employing liquid chromatography-high resolution-tandem mass spectrometry for the quantification of trimetazidine, lomerizine and the specific metabolite bis-(4-fluorophenyl)-methylpiperazine (M6) in urine was developed. An oral dose of 15mg was administered to 10 male volunteers, after which urine samples collected during the following 276hours were analyzed using the developed method, allowing for examination of the target analytes' excretion profile. The limit of detection of all target analytes was <0.02ng/mL. In all volunteers, the metabolite M6 was detected up to 276hours after administration. After more than 12hours, all volunteers were found to have higher concentrations of the metabolite M6 than of trimetazidine. The concentrations of trimetazidine, lomerizine, M6, and the M6/trimetazidine ratio in the final sample collected after 276hours were 0.2-0.9ng/mL, <0.05-0.1ng/mL, 14.1-38.3ng/mL, and 28.8-122.9, respectively. The urinary excretion of trimetazidine, unchanged lomerizine, and the metabolite M6 within the first 276hours was 0.64%, 0.006%, and 6.1%, respectively. Consequently, the absence of the metabolite M6 in doping control urine samples corroborates the conclusion that lomerizine is unlikely to be the source of trimetazidine. The results confirm that the M6 metabolite is the longest-lasting urinary metabolite of lomerizine currently known.