In:
Basic & Clinical Pharmacology & Toxicology, Wiley, Vol. 120, No. 5 ( 2017-05), p. 450-456
Abstract:
Meldonium (3‐(2,2,2‐trimethylhydrazinium)propionate) is the most potent clinically used inhibitor of organic cation transporter 2 ( OCTN 2). Inhibition of OCTN 2 leads to a decrease in carnitine and acylcarnitine contents in tissues and energy metabolism optimization‐related cardioprotective effects. The recent inclusion of meldonium in the World Anti‐Doping Agency List of Prohibited Substances and Methods has raised questions about the pharmacokinetics of meldonium and its unusually long elimination time. Therefore, in this study, the rate of meldonium washout after the end of the treatment was tested with and without administration of carnitine, γ‐butyrobetaine ( GBB ) and furosemide to evaluate the importance of competition for OCTN 2 transport in mice. Here, we show that carnitine and GBB administration during the washout period effectively stimulated the elimination of meldonium. GBB induced a more pronounced effect on meldonium elimination than carnitine due to the higher affinity of GBB for OCTN 2. The diuretic effect of furosemide did not significantly affect the elimination of meldonium, carnitine and GBB . In conclusion, the competition of meldonium, carnitine and GBB for OCTN 2‐mediated transport determines the pharmacokinetic properties of meldonium. Thus, due to their affinity for OCTN 2, GBB and carnitine but not furosemide stimulated meldonium elimination. During long‐term treatment, OCTN 2‐mediated transport ensures a high muscle content of meldonium, while tissue clearance depends on relatively slow diffusion, thus resulting in the unusually long complete elimination period of meldonium.
Type of Medium:
Online Resource
ISSN:
1742-7835
,
1742-7843
DOI:
10.1111/bcpt.2017.120.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2151592-X
SSG:
15,3
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