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Chinese Journal of Chromatography
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Chinese Journal of Chromatography  2019, Vol. 37 Issue (6): 581-588    DOI: 10.3724/SP.J.1123.2019.01008
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Simultaneous determination of leucovorin and 5-methyl-tetrahydrofolate diastereoisomers in human plasma by high-performance liquid chromatography-tandem mass spectrometry coupled with ultrafiltration centrifugation-based pretreatment and its application to a pharmacokinetic study
XU Chenfeng1, HUI Wenkai2, SUN Lili3, GAO Qianqian3, ZOU Qiaogen1
1. Nanjing Tech University, Nanjing 211800, China;
2. Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Lianyungang 222000, China;
3. Nanjing Healthnice Medical Technology Co., Ltd, Nanjing 210009, China
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Abstract 

A simple, sensitive, and stable high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the simultaneous determination of leucovorin and 5-methyltetrahydrofolate diastereomers in human plasma using methotrexate as the internal standard. The analytes and the internal standard were extracted from plasma samples by simple ultrafiltration centrifugation-based extraction. The separation was achieved on a chiral HSA column (150 mm×4 mm, 5 μm) using mobile phases containing 10 mmol pH 8.0 ammonium acetate and acetonitrile in gradient mode. The method showed good linearities in the ranges of 25-5000 μg/L and 12.5-3000 μg/L for leucovorin and 5-methyltetrahydrofolate diastereoisomers, respectively. The method was fully validated with respect to sensitivity, precision, accuracy, matrix effect, extraction recovery, and stability of analytes under various conditions. The method was successfully applied to a pharmacokinetic study of 125 mg/m2 6R,S-leucovorin and 62.5 mg/m2 6S-leucovorin. The results showed that the maximum observed concentrations (Cmax) of 6S-leucovorin and L-5-methyltetrahydrofolate were (3137.917±408.837) and (1679.633±244.132) μg/L, respectively, and the areas under the curve from the time of dosing to the last measurable concentration (AUC0-t) were (7504.883±1185.101) and (14001.214±2868.949) μg/L in the 125 mg/m2 6R,S-leucovorin dose group. The Cmax values of 6S-leucovorin and L-5-methyltetrahydrofolate were (3187.917±387.298) and (1739.204±224.755) μg/L, respectively, and AUC0-t values were (7426.664±854.825) and (14884.331±1843.353) μg/L in the 62.5 mg/m2 6S-leucovorin dose group. There were no significant diffe-rences in the main pharmacokinetic parameters between the two dose groups, and the pharmacokinetic characteristics as well as the rate and extent of absorption were consistent. This method can provide technical support for future bioequivalence studies of sodium leucovorin.

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Articles by authors
XU Chenfeng
HUI Wenkai
SUN Lili
GAO Qianqian
ZOU Qiaogen
Key wordshigh-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)   ultrafiltration centrifugation   leucovorin (LV)   pharmacokinetics   chiral separation     
Received: 2019-01-07;
Cite this article:   
XU Chenfeng,HUI Wenkai,SUN Lili et al. Simultaneous determination of leucovorin and 5-methyl-tetrahydrofolate diastereoisomers in human plasma by high-performance liquid chromatography-tandem mass spectrometry coupled with ultrafiltration centrifugation-based pretreatment and its application to a pharmacokinetic study[J]. Chinese Journal of Chromatography, 2019, 37(6): 581-588.
 
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