Determination of mildronate by LC–MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers

Ye, Peng; Yang, Jing; Zhi-rui, Wang; Wang, Jingwen; Liu, Yu; Luo, Zhuojing; Wen, Aidong

doi:10.1016/j.jchromb.2009.12.030

Cited by 37 publications

(43 citation statements)

References 5 publications

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“…Moreover, a study in rats demonstrated that the PK of mildronate was nonlinear, which was consistent with the result of our research in healthy Chinese humans [5]. However, the new article in the Journal of Chromatography B reported the linear dynamics of mildronate injection [6]; this result was excluded by our research. Therefore, the preliminary conclusion that mildronate has nonlinear PK in humans is made.…”

Section: Discussionsupporting

confidence: 88%

Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open‐label, single‐ and multiple‐dose study in healthy volunteers

Jun

Cai

Yang

et al. 2011

Fundamemntal Clinical Pharma

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Mildronate has been used as antianginal drug in parts of Europe for many years, but its pharmacokinetic (PK) properties in humans remain unclear. This study was designed to assess and compare the PK properties of mildronate capsules after single escalating oral dose and multiple doses in healthy Chinese volunteers. Volunteers were randomly assigned to receive a single dose of 250, 500, 1000, 1250 or 1500 mg of mildronate capsules. Those who received the 500-mg dose continued on the multiple-dose phase and received 500 mg three times a day for 13 days. Plasma drug concentrations were analysed by ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Tolerability was assessed throughout the study. A total of 40 Chinese volunteers were enrolled in the study. No period or sequence effect was observed. Area under the concentration and C(max) were increased proportionally with the dose levels, whereas t(1/2) and V(d)/f were dependent on the dose. Nonlinear PK properties were found at doses of 250-1500 mg. There was an accumulation after multiple-dose administration. No serious adverse events (AEs) were reported in the PK study. The formulation was well tolerated.

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Section: Discussionsupporting

confidence: 88%

Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open‐label, single‐ and multiple‐dose study in healthy volunteers

Jun

Cai

Yang

et al. 2011

Fundamemntal Clinical Pharma

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“…For the ingestion of meldonium capsules (single oral dose up to 1500 mg or 500 mg three times a day for 13 consecutive days), the respective t1/2 values were 6.58±0.91 hours and 14.60±2.52 hours, indicating the accumulation of meldonium after multidose oral application 57. After a single intravenous injection of meldonium (1000 mg), the plasma elimination t1/2 was 6.55±1.17 hours 58. After a multidose administration (500 mg injection for 6 consecutive days), the t1/2 of meldonium was increased to 15.34±3.14 hours, indicating plasma accumulation of meldonium after repeated injections.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Recent reports from the World Anti-Doping Agency (WADA) indicate an alarming prevalence in the use of meldonium among elite athletes. Therefore, in January 2016, meldonium was added to WADA's prohibited list after being monitored since 2015. Meldonium has been shown to have beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective properties, which are ascribed mainly to its inhibition of ß-oxidation and its activation of glycolysis. Despite its widespread use, there are only a few clinical studies or clinical trials available. Meldonium is registered in most Baltic countries and is easily accessible through the internet with no serious adverse effects reported by the manufacturer so far. Among athletes, meldonium is used with the purpose of increasing recovery rate or exercise performance. The benefit of taking meldonium in view of performance enhancement in athletes is quite speculative and is discussed without sound scientific evidence. This narrative review provides a detailed overview of the drug meldonium, focusing on the main topics pharmacology and biochemical actions, clinical applications, pharmacokinetics, methods of detection and potential for performance enhancement in athletes.

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“…The curves were fitted by a weighted (1/x) least-squares linear regression method through the measurement of the peak area ratio of the analyte to IS. The acceptance criterion for the correlation coefficient (r) of the calibration curve should be larger than 0.999 and that of each back-calculated standard concentration must be within 15% deviation from the nominal value except at the LLOQ [12]. The lower limit of quantification (LLOQ) was defined as the lowest concentration in the standard curve at which the signal-to-noise ratio (S/N) was preliminarily found to be larger than five, the relative standard deviation (RSD) (n = 6) was within 20%, and the relative error (RE) was within ±20% [11].…”

Section: Methods Validationmentioning

confidence: 99%

Quantitative Determination of Anti-Inflammatory Columbianetin in Rat Plasma by LC-ESI-MS/MS for Pharmacokinetic Studies after Oral Administration of Duhuo Extract

Chang

Zhu

et al. 2011

Chromatographia

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Specific LC-ESI-MS/MS method or procedure was developed and validated for columbianetin quantification in rat plasma using epicatechin as an internal standard (IS). Chromatographic separation was performed on an Eclipse plus C18 (150 9 4.6 mm, 1.8 lm) at a flow rate of 0.300 mL min -1 , and water-acetonitrile was used as mobile phase. The calibration curve of the method was linear in the concentration range of 5-1,000 ng mL -1 . The lower limit of quantification (LLOQ) was 5 ng mL -1 . The intra-and inter-day precision of the quality control samples was within 15.0%, and the accuracy was within 90.0-110%. The recoveries were more than 90.0% for columbianetin at concentrations of 10, 200 and 1,000 ng mL -1 , respectively. This method was successfully applied for evaluation of the pharmacokinetics of columbianetin after oral doses of 0.60 g kg -1 Angelica pubescence extract in rats.

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Determination of mildronate by LC–MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers

Cited by 37 publications

References 5 publications

Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open‐label, single‐ and multiple‐dose study in healthy volunteers

Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open‐label, single‐ and multiple‐dose study in healthy volunteers

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

Quantitative Determination of Anti-Inflammatory Columbianetin in Rat Plasma by LC-ESI-MS/MS for Pharmacokinetic Studies after Oral Administration of Duhuo Extract

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