Story behind meldonium–from pharmacology to performance enhancement: a narrative review

Although developed as a therapeutic medication, meldonium has found widespread use in human sports and was recently added to the World Anti-Doping Agency's list of prohibited substances. Its reported abuse potential in human sports has led to concern by regulatory authorities about the possible misuse of meldonium in equine athletics. The potential abuse in equine athletes along with the limited data available regarding the pharmacokinetics and pharmacodynamics of meldonium in horses necessitates further study. Eight exercised adult thoroughbred horses received a single oral dose of 3.5, 7.1, 14.3 or 21.4 mg/kg of meldonium. Blood and urine samples were collected and analyzed using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using non-compartmental analysis. Maximum serum concentrations ranged from 440.2 to 1147 ng/mL and the elimination half-life from 422 to 647.8 h. Serum concentrations were below the limit of quantitation by days 4, 7, 12 and 12 for doses of 3.5, 7.1, 14.3 and 21.4 mg/kg, respectively. Urine concentrations were below the limit of detection by day 44 following administration of 3.5 mg/kg and day 51 for all other dose groups. No adverse effects were observed following meldonium administration. While the group numbers were small, changes in heart rate were observed in the 3.5 mg/kg dose group (n = 1). Glucose concentrations changed significantly in all dose groups studied (n = 2 per dose group). Similar to that reported for humans, the detection time of meldonium in biological samples collected from horses is prolonged, which should allow for satisfactory regulation in performance horses.

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses

Knych

Stanley

McKemie

et al. 2017

“…While the meldonium's potential to enhance athletic performance has continued to be the subject of debate, its retention, particularly in muscle tissue following long‐term treatment, has recently been proven in an animal model . Mice received meldonium orally at 400 mg/kg/day over a period of 2 weeks, and the effects of ‐butyrobetaine (GBB), carnitine, and furosemide on the elimination of the drug were studied.…”

Section: Hormone and Metabolic Modulatorsmentioning

confidence: 99%

Annual banned‐substance review: Analytical approaches in human sports drug testing

Thevis

Kuuranne

Geyer

2017

Several high-profile revelations concerning anti-doping rule violations over the past 12 months have outlined the importance of tackling prevailing challenges and reducing the limitations of the current anti-doping system. At this time, the necessity to enhance, expand, and improve analytical test methods in response to the substances outlined in the World Anti-Doping Agency's (WADA) Prohibited List represents an increasingly crucial task for modern sports drug-testing programs. The ability to improve analytical testing methods often relies on the expedient application of novel information regarding superior target analytes for sports drug-testing assays, drug elimination profiles, alternative test matrices, together with recent advances in instrumental developments. This annual banned-substance review evaluates literature published between October 2016 and September 2017 offering an in-depth evaluation of developments in these arenas and their potential application to substances reported in WADA's 2017 Prohibited List.

“…Consequently, the meldonium excretion period in healthy athlete volunteers and the substance's long‐term urine and blood plasma pharmacokinetics became central questions for the anti‐doping community to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, information on pharmacokinetics of meldonium, especially data on long‐term excretion of high oral doses have been limited to a few studies . It was shown that after oral administration of meldonium, a non‐linear response profile and a two‐phase excretion was observed for 65 and 117 days.…”

Section: Introductionmentioning

confidence: 99%

Meldonium long‐term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers

Rabin

Уйба

Miroshnikova

et al. 2018

Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti‐Doping Agency Monitoring Program. In the early months of 2016, anti‐doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of meldonium. Consequently, the meldonium excretion period in healthy athletes and the substance's long‐term urine and blood (plasma) pharmacokinetics became central questions for the anti‐doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on meldonium pharmacokinetics is limited to a few studies, with no known data available on long‐term excretion of high oral doses. The primary objective of this open‐label study was to determine long‐term urine and plasma pharmacokinetic parameters of meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L‐carnitine administration on meldonium excretion and pharmacokinetics. Thirty‐two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral meldonium daily for 3 weeks. The study found meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.