Urinary excretion studies of meldonium after multidose parenteral application

• Published in: Journal of pharmaceutical and biomedical analysis 2018-11, Vol.161, p.289-295
• Main Authors: Forsdahl, Guro, Jančić-Stojanović, Biljana, Anđelković, Marija, Dikić, Nenad, Geisendorfer, Tomas, Jeitler, Veronika, Gmeiner, Günter
• Format: Article
• Language: English
• Subjects: Adult; Chromatography, Liquid - methods; Doping analysis; Female; Half-Life; Humans; Injections, Intravenous; Male; Meldonium; Methylhydrazines - administration & dosage; Methylhydrazines - urine; Middle Aged; Models, Biological; Pharmacokinetics; Substance Abuse Detection - methods; Tandem Mass Spectrometry - methods; Urinary excretion
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2018.08.053

[Display omitted] •Meldonium has a potential performance enhancing effect in sports.•The urinary analysis is based on HILIC MS/MS.•For the first time, the long-term excretion of meldonium after multiple parenteral administration was investigated.•Meldonium can be detected in urine for several months after parenteral administration.•A three-compartment model best describes meldoniums pharmacokinetics. Meldonium is a drug exhibiting cardioprotective and anti-ischemic effects. Due to its potential performance-enhancing benefit in sports, meldonium was added to the World Anti-Doping Agency list of prohibited substances in 2016. Since then, a high number of adverse analytical findings reported on meldonium has questioned meldonium`s detection time in urine. Hence, the objective of the current study was to characterize the pharmacokinetic urinary excretion pattern of meldonium when administered as multiple intravenous injections. Three injections of 250 mg meldonium were given over a time period of five days to six healthy volunteers and urine samples were collected for eight months after the last injection of the drug. For the quantification of meldonium in urine, a liquid chromatography-tandem mass spectrometry method was fully validated according to the World Anti-Doping Agency guidelines in terms of specificity, matrix interferences, intra- and inter-day precision, accuracy, carry-over, robustness, linearity, limit of detection, and limit of quantification. The assay was successfully applied to the pharmacokinetic study. A three-compartment model was found to best describe the pharmacokinetics of meldonium with average alpha, beta, and gamma half-lives of 1.4 h, 9.4 h, and 655 h, respectively. The detection time in urine varied between 94 and 162 days.