Post by Admin on Feb 15, 2022 18:38:42 GMT
ANALYSIS AND REPORTING OF TRIMETAZIDINE FINDINGS
The World Anti-Doping Agency wishes to draw the attention of the Laboratories to the following
remarks and instructions on the analysis and reporting of trimetazidine (TMZ).
The detection of TMZ [1-(2,3,4-trimethoxybenzyl)piperazine] in urine may result from the metabolism
of lomerizine [1-[bis(4-fluorophenyl)methyl-4-(2,3,4-trimethoxybenzyl)piperazine], a permitted drug
used for the treatment of migraine.1,2,3
Note: Lomerizine (the parent compound), which has a short half-life, can be found in urine at concentrations
much lower than that of TMZ (minor Metabolite), in a ratio of 1/20 or less. However, the concentration of the
lomerizine M6-Metabolite is usually higher than that of TMZ.
Therefore, when detecting TMZ in urine, Laboratories shall:
1. Test for the presence of the non-prohibited lomerizine AND its specific Metabolite(s) [at least the
N-dealkylated M6 Metabolite, 1-Bis-(4-fluorophenyl)-methylpiperazine] 4 using e.g. LC-MS/MS
targeting the diagnostic precursor/product ion pairs shown below, which are obtained from the
protonated molecules of TMZ, lomerizine and lomerizine M6-Metabolite;
2. Report the result as a Negative Finding if it is considered that the presence of TMZ in the
Sample could have resulted from the permitted administration of lomerizine;
3. When reporting an Adverse Analytical Finding for TMZ, include a comment in the Test Report
specifying “Neither lomerizine nor its Metabolite(s) (at least M6) were detected in the Sample".
Should you have any further questions, please do not hesitate to contact the WADA Science
Department.
4 The reference standards for lomerizine and its M6 Metabolite can be purchased from Sigma-Aldrich (L6295 and 552402, respectively) 5 Ren Y et al. “Determination of lomerizine in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study”. J Chromatogr B Analyt Technol Biomed Life Sci. 947-948: 96-102,
2014. www.sigmaaldrich.com/catalog/product/aldrich/552402?lang=en®ion=CA
Transition (m/z)3, 5
Trimetazidine Lomerizine Lomerizine M6-Metabolite
267>181 469>181 289>203
267>166 469>203 289>183
267>136 469>166
Note: The Limit of Detection (LOD) of the Tests Method(s) used for the detection of lomerizine and its M6
Metabolite should be lower than the corresponding LOD for TMZ.
2. Report the result as a Negative Finding if it is considered that the presence of TMZ in the
Sample could have resulted from the permitted administration of lomerizine;
3. When reporting an Adverse Analytical Finding for TMZ, include a comment in the Test Report
specifying “Neither lomerizine nor its Metabolite(s) (at least M6) were detected in the Sample".
The World Anti-Doping Agency wishes to draw the attention of the Laboratories to the following
remarks and instructions on the analysis and reporting of trimetazidine (TMZ).
The detection of TMZ [1-(2,3,4-trimethoxybenzyl)piperazine] in urine may result from the metabolism
of lomerizine [1-[bis(4-fluorophenyl)methyl-4-(2,3,4-trimethoxybenzyl)piperazine], a permitted drug
used for the treatment of migraine.1,2,3
Note: Lomerizine (the parent compound), which has a short half-life, can be found in urine at concentrations
much lower than that of TMZ (minor Metabolite), in a ratio of 1/20 or less. However, the concentration of the
lomerizine M6-Metabolite is usually higher than that of TMZ.
Therefore, when detecting TMZ in urine, Laboratories shall:
1. Test for the presence of the non-prohibited lomerizine AND its specific Metabolite(s) [at least the
N-dealkylated M6 Metabolite, 1-Bis-(4-fluorophenyl)-methylpiperazine] 4 using e.g. LC-MS/MS
targeting the diagnostic precursor/product ion pairs shown below, which are obtained from the
protonated molecules of TMZ, lomerizine and lomerizine M6-Metabolite;
2. Report the result as a Negative Finding if it is considered that the presence of TMZ in the
Sample could have resulted from the permitted administration of lomerizine;
3. When reporting an Adverse Analytical Finding for TMZ, include a comment in the Test Report
specifying “Neither lomerizine nor its Metabolite(s) (at least M6) were detected in the Sample".
Should you have any further questions, please do not hesitate to contact the WADA Science
Department.
4 The reference standards for lomerizine and its M6 Metabolite can be purchased from Sigma-Aldrich (L6295 and 552402, respectively) 5 Ren Y et al. “Determination of lomerizine in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study”. J Chromatogr B Analyt Technol Biomed Life Sci. 947-948: 96-102,
2014. www.sigmaaldrich.com/catalog/product/aldrich/552402?lang=en®ion=CA
Transition (m/z)3, 5
Trimetazidine Lomerizine Lomerizine M6-Metabolite
267>181 469>181 289>203
267>166 469>203 289>183
267>136 469>166
Note: The Limit of Detection (LOD) of the Tests Method(s) used for the detection of lomerizine and its M6
Metabolite should be lower than the corresponding LOD for TMZ.
2. Report the result as a Negative Finding if it is considered that the presence of TMZ in the
Sample could have resulted from the permitted administration of lomerizine;
3. When reporting an Adverse Analytical Finding for TMZ, include a comment in the Test Report
specifying “Neither lomerizine nor its Metabolite(s) (at least M6) were detected in the Sample".