Development of a UPLC-MS/MS Assay for the Quantitative Determination of Capecitabine, 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5'-fluorouracil (5-FU), and α-fluoro-β-alanine (FBAL).

IF 1.5 4区医学 Q4 CHEMISTRY, MEDICINAL Pharmazie Pub Date : 2023-08-01 DOI:10.1691/ph.2023.3001

J E Knikman, Niels de Vries, H Rosing, A Cats, H-J Guchelaar, J H Beijnen

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Abstract

Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-β-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples. Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-β-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples.

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建立卡培他滨、5′-脱氧-5-氟胞苷(5′-dFCR)、5′-脱氧-5-氟吡啶(5′-dFUR)、5′-氟尿嘧啶(5- fu)和α-氟-β-丙氨酸(FBAL)的UPLC-MS/MS定量测定方法。

卡培他滨是一种抗癌药物，是5-氟尿嘧啶(5-FU)的口服前药。本研究建立了一种超高效液相色谱-涡流喷雾串联质谱(UPLC-MS/MS)方法，用于定量卡培他滨及其代谢产物5′-脱氧-5-氟胞苷(5′-dFCR)、5′-脱氧-5-氟吡啶(5′-dFUR)、5- fu和氟β-丙氨酸(FBAL)。分析物采用蛋白沉淀法提取，采用Acquity UPLC HSS T3柱梯度洗脱进行色谱分离，采用电喷雾电离源串联质谱仪进行分析。卡培他滨和5’-dFCR在正离子模式下定量，5’-dFUR、5- fu和FBAL在负离子模式下定量。总色谱运行时间为9分钟。所有分析物均使用稳定同位素标记的内标。在人血浆中卡培他滨25.0 ~ 2500 ng/mL,5’-dFCR、5’-dFUR和5- fu 10.0 ~ 1000 ng/mL, FBAL 50 ~ 5000 ng/mL范围内验证了该方法。验证结果表明，开发的分析方法可以可靠地定量分析血浆样品中的卡培他滨、5'-dFCR、5'-dFUR、5- fu和FBAL。卡培他滨是一种抗癌药物，是5-氟尿嘧啶(5-FU)的口服前药。本研究建立了一种超高效液相色谱-涡流喷雾串联质谱(UPLC-MS/MS)方法，用于定量卡培他滨及其代谢产物5′-脱氧-5-氟胞苷(5′-dFCR)、5′-脱氧-5-氟吡啶(5′-dFUR)、5- fu和氟β-丙氨酸(FBAL)。分析物采用蛋白沉淀法提取，采用Acquity UPLC HSS T3柱梯度洗脱进行色谱分离，采用电喷雾电离源串联质谱仪进行分析。卡培他滨和5’-dFCR在正离子模式下定量，5’-dFUR、5- fu和FBAL在负离子模式下定量。总色谱运行时间为9分钟。所有分析物均使用稳定同位素标记的内标。在人血浆中卡培他滨25.0 ~ 2500 ng/mL,5’-dFCR、5’-dFUR和5- fu 10.0 ~ 1000 ng/mL, FBAL 50 ~ 5000 ng/mL范围内验证了该方法。验证结果表明，开发的分析方法可以可靠地定量分析血浆样品中的卡培他滨、5'-dFCR、5'-dFUR、5- fu和FBAL。

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来源期刊

Pharmazie 医学-化学综合

CiteScore

3.10

自引率

0.00%

发文量

审稿时长

1.2 months

期刊介绍： The journal DiePharmazie publishs reviews, experimental studies, letters to the editor, as well as book reviews. The following fields of pharmacy are covered: Pharmaceutical and medicinal chemistry; Pharmaceutical analysis and drug control; Pharmaceutical technolgy; Biopharmacy (biopharmaceutics, pharmacokinetics, biotransformation); Experimental and clinical pharmacology; Pharmaceutical biology (pharmacognosy); Clinical pharmacy; History of pharmacy.