Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses

Abstract

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.

Meldonium: Pharmacological, toxicological, and analytical aspects

“…6,59,60 Total blood, plasma, and serum samples for meldonium determination were used for other approaches, mainly pharmacokinetics, pharmacodynamics, bioequivalence, and biochemical studies. 19,20,24,32,[61][62][63][64] There are no scientific papers that have used alternative biological matrices, such as hair, nails, sweat, or oral fluid, despite the viability of these matrices, especially oral fluid (because meldonium lacks affinity for plasma proteins).…”

“…Most studies use urine samples to determine meldonium concentration. For this specific biological matrix, dilutions with different solvents and combinations were evaluated in specific proportions, including acetonitrile:ammonium acetate, 60,65 acetonitrile:ammonium formate, 24,61 deionized water 58,60 or deionized water followed by an acetonitrile:methanol mixture. 32,51 Lv et al 63 did not dilute urine samples, but rather mixed them with an internal standard solution and centrifuged the mixture to remove large particles.…”

“…Since meldonium is highly soluble in water, active transport in the gastrointestinal tract becomes very important, and saturation of these transporters could lead to this kinetics. 24 Tretzel et al 26 orally administered a single dose (500 mg) or multiple doses (3 Â 500 mg/day for 6 consecutive days) of meldonium and evaluated the substance concentration by dried blood spot (DBS). DBS method is a form of biosampling where blood samples are blotted and dried on a specific filter paper, with positive results after 16 days for a single dose or 28 days for multiple doses.…”

Advances in equine anti‐doping

“…On the ‘small molecule’ front these cover in vitro phase I metabolic studies of the selective estrogen receptor modulators (SERMs) tamoxifen and toremifene, and population studies of 5‐Aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) in the horse . Equine pharmacokinetic studies are well represented with a focus on methylxanthines, betamethasone, and meldonium …”

“…[8] Equine pharmacokinetic studies are well represented with a focus on methylxanthines, [9] betamethasone, [10] and meldonium. [11] Recent progress in inductively coupled plasma mass spectrometry (ICP-MS) analysis is highlighted by the large-scale collaborative work of Popot et al [12] presenting interlaboratory reproducibility for the measurement of cobalt in equine urine and plasma. The scope of trace elements of interest to racing continues to expand with Choi et al [13] reporting the application of lithium analysis for equine urine and plasma samples to propose a urinary threshold of 5 μg/mL.…”