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Evaluation of dried blood spots as an alternative sampling strategy for 5-fluorouracil monitoring: From method development to clinical application
Therapeutic drug monitoring (TDM) of 5-Fluorouracil (5-FU) is strongly recommended because of its large inter-individual pharmacokinetic variability, narrow therapeutic window, and incidence of toxicity. However, there are several factors that limit the application of TDM in clinical settings. Consi...
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Published in: | Journal of pharmaceutical and biomedical analysis 2023-10, Vol.235, p.115539-115539, Article 115539 |
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description | Therapeutic drug monitoring (TDM) of 5-Fluorouracil (5-FU) is strongly recommended because of its large inter-individual pharmacokinetic variability, narrow therapeutic window, and incidence of toxicity. However, there are several factors that limit the application of TDM in clinical settings. Considering the intrinsic advantages of dried microsamples, such as minimally invasive sampling, analyte stability, and cost-effective logistics, this study aimed to develop a method for the determination of 5-FU in dried blood spots (DBS) using ultra-high liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and to evaluate its clinical application. Sample preparation was based on an aqueous extraction followed by protein precipitation. Separation was performed in an Acquity UPLC® HSS C18 (150 ×2.1 mm, 1.8 µm), and the mobile phases were water and acetonitrile with 0.5% acetic acid. The total run time was 5.5 min. The method was linear from 100 to 2000 ng/mL, precise (maximum CV% of 7.5%), and accurate (98.3–115.4%). The average recovery was 70%. Blood hematocrit had a minimal impact on the assay. DBS samples were stable for 21 days at 4, 25, and 45 °C. A total of 40 paired samples of plasma, capillary DBS, and venous DBS were analyzed. Median 5-FU concentrations were 444.7, 637.0, and 499.7 ng/mL for plasma, capillary DBS, and venous DBS, respectively. Capillary and plasma concentrations were significantly correlated (r > 0.90), but there was a lack of agreement between the methods, as capillary DBS levels were on average 146% of plasma. Venous DBS corresponded to 110% of the measured plasma concentrations, with a strong correlation (r > 0.97) and agreement between the methods. Our study is the first to report the use of DBS samples to quantify 5-FU. Further studies are needed to establish whether capillary samples can replace plasma.
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•5-Fluorouracil can be quantified in DBS using UHPLC–MS/MS.•Venous DBS can be used as alternative samples for 5-Fluorouracil TDM.•5-Fluorouracil is stable in DBS samples stored at 4, 25, and 45 °C for 21 days. |
doi_str_mv | 10.1016/j.jpba.2023.115539 |
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[Display omitted]
•5-Fluorouracil can be quantified in DBS using UHPLC–MS/MS.•Venous DBS can be used as alternative samples for 5-Fluorouracil TDM.•5-Fluorouracil is stable in DBS samples stored at 4, 25, and 45 °C for 21 days.</description><identifier>ISSN: 0731-7085</identifier><identifier>EISSN: 1873-264X</identifier><identifier>DOI: 10.1016/j.jpba.2023.115539</identifier><identifier>PMID: 37517245</identifier><language>eng</language><publisher>England: Elsevier B.V</publisher><subject>5-Fluorouracil ; Dried blood spots ; Therapeutic drug monitoring ; UHPLC-MS/MS</subject><ispartof>Journal of pharmaceutical and biomedical analysis, 2023-10, Vol.235, p.115539-115539, Article 115539</ispartof><rights>2023 Elsevier B.V.</rights><rights>Copyright © 2023 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-414393ca187c081d85049446138f9b55cc6156a6c7eb2a2b9ec486da42545ac3</citedby><cites>FETCH-LOGICAL-c356t-414393ca187c081d85049446138f9b55cc6156a6c7eb2a2b9ec486da42545ac3</cites><orcidid>0000-0003-0632-7955</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37517245$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>da Silva, Laura C.</creatorcontrib><creatorcontrib>Grando, Ana P.</creatorcontrib><creatorcontrib>de Baco, Lucas S.</creatorcontrib><creatorcontrib>Hahn, Roberta Z.</creatorcontrib><creatorcontrib>Ferreira Filho, Antônio F.</creatorcontrib><creatorcontrib>Brucker, Natália</creatorcontrib><creatorcontrib>Linden, Rafael</creatorcontrib><creatorcontrib>Antunes, Marina V.</creatorcontrib><title>Evaluation of dried blood spots as an alternative sampling strategy for 5-fluorouracil monitoring: From method development to clinical application</title><title>Journal of pharmaceutical and biomedical analysis</title><addtitle>J Pharm Biomed Anal</addtitle><description>Therapeutic drug monitoring (TDM) of 5-Fluorouracil (5-FU) is strongly recommended because of its large inter-individual pharmacokinetic variability, narrow therapeutic window, and incidence of toxicity. However, there are several factors that limit the application of TDM in clinical settings. Considering the intrinsic advantages of dried microsamples, such as minimally invasive sampling, analyte stability, and cost-effective logistics, this study aimed to develop a method for the determination of 5-FU in dried blood spots (DBS) using ultra-high liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and to evaluate its clinical application. Sample preparation was based on an aqueous extraction followed by protein precipitation. Separation was performed in an Acquity UPLC® HSS C18 (150 ×2.1 mm, 1.8 µm), and the mobile phases were water and acetonitrile with 0.5% acetic acid. The total run time was 5.5 min. The method was linear from 100 to 2000 ng/mL, precise (maximum CV% of 7.5%), and accurate (98.3–115.4%). The average recovery was 70%. Blood hematocrit had a minimal impact on the assay. DBS samples were stable for 21 days at 4, 25, and 45 °C. A total of 40 paired samples of plasma, capillary DBS, and venous DBS were analyzed. Median 5-FU concentrations were 444.7, 637.0, and 499.7 ng/mL for plasma, capillary DBS, and venous DBS, respectively. Capillary and plasma concentrations were significantly correlated (r > 0.90), but there was a lack of agreement between the methods, as capillary DBS levels were on average 146% of plasma. Venous DBS corresponded to 110% of the measured plasma concentrations, with a strong correlation (r > 0.97) and agreement between the methods. Our study is the first to report the use of DBS samples to quantify 5-FU. Further studies are needed to establish whether capillary samples can replace plasma.
[Display omitted]
•5-Fluorouracil can be quantified in DBS using UHPLC–MS/MS.•Venous DBS can be used as alternative samples for 5-Fluorouracil TDM.•5-Fluorouracil is stable in DBS samples stored at 4, 25, and 45 °C for 21 days.</description><subject>5-Fluorouracil</subject><subject>Dried blood spots</subject><subject>Therapeutic drug monitoring</subject><subject>UHPLC-MS/MS</subject><issn>0731-7085</issn><issn>1873-264X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kT1vFDEQhi0EIkfgD1AglzR7-HM_EA2KEkCKRJOCzpq1Z4NP3vVie0_K38gvxscFSqSRpnnm0cy8hLzlbM8Zbz8c9od1hL1gQu4511oOz8iO951sRKt-PCc71knedKzXF-RVzgfGmOaDekkuZKd5J5TekcfrI4QNio8LjRN1yaOjY4jR0bzGkinUWiiEgmmp2BFphnkNfrmnuSQoeP9Ap5iobqawxRS3BNYHOsfFl5gq9pHepDjTGcvPKnV4xBDXGZdCS6S2iryFQGGtTvtnj9fkxQQh45unfknubq7vrr42t9-_fLv6fNtYqdvSKK7kIC3Ugy3rues1U4NSLZf9NIxaW9ty3UJrOxwFiHFAq_rWgRJaabDykrw_a9cUf22Yi5l9thgCLBi3bESvFBsYE6qi4ozaFHNOOJk1-RnSg-HMnKIwB3OKwpyiMOco6tC7J_82zuj-jfz9fQU-nQGsRx49JpOtx8Wi8wltMS76__l_A-SKnP0</recordid><startdate>20231025</startdate><enddate>20231025</enddate><creator>da Silva, Laura C.</creator><creator>Grando, Ana P.</creator><creator>de Baco, Lucas S.</creator><creator>Hahn, Roberta Z.</creator><creator>Ferreira Filho, Antônio F.</creator><creator>Brucker, Natália</creator><creator>Linden, Rafael</creator><creator>Antunes, Marina V.</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0632-7955</orcidid></search><sort><creationdate>20231025</creationdate><title>Evaluation of dried blood spots as an alternative sampling strategy for 5-fluorouracil monitoring: From method development to clinical application</title><author>da Silva, Laura C. ; Grando, Ana P. ; de Baco, Lucas S. ; Hahn, Roberta Z. ; Ferreira Filho, Antônio F. ; Brucker, Natália ; Linden, Rafael ; Antunes, Marina V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-414393ca187c081d85049446138f9b55cc6156a6c7eb2a2b9ec486da42545ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>5-Fluorouracil</topic><topic>Dried blood spots</topic><topic>Therapeutic drug monitoring</topic><topic>UHPLC-MS/MS</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>da Silva, Laura C.</creatorcontrib><creatorcontrib>Grando, Ana P.</creatorcontrib><creatorcontrib>de Baco, Lucas S.</creatorcontrib><creatorcontrib>Hahn, Roberta Z.</creatorcontrib><creatorcontrib>Ferreira Filho, Antônio F.</creatorcontrib><creatorcontrib>Brucker, Natália</creatorcontrib><creatorcontrib>Linden, Rafael</creatorcontrib><creatorcontrib>Antunes, Marina V.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>da Silva, Laura C.</au><au>Grando, Ana P.</au><au>de Baco, Lucas S.</au><au>Hahn, Roberta Z.</au><au>Ferreira Filho, Antônio F.</au><au>Brucker, Natália</au><au>Linden, Rafael</au><au>Antunes, Marina V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of dried blood spots as an alternative sampling strategy for 5-fluorouracil monitoring: From method development to clinical application</atitle><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle><addtitle>J Pharm Biomed Anal</addtitle><date>2023-10-25</date><risdate>2023</risdate><volume>235</volume><spage>115539</spage><epage>115539</epage><pages>115539-115539</pages><artnum>115539</artnum><issn>0731-7085</issn><eissn>1873-264X</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Therapeutic drug monitoring (TDM) of 5-Fluorouracil (5-FU) is strongly recommended because of its large inter-individual pharmacokinetic variability, narrow therapeutic window, and incidence of toxicity. However, there are several factors that limit the application of TDM in clinical settings. Considering the intrinsic advantages of dried microsamples, such as minimally invasive sampling, analyte stability, and cost-effective logistics, this study aimed to develop a method for the determination of 5-FU in dried blood spots (DBS) using ultra-high liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and to evaluate its clinical application. Sample preparation was based on an aqueous extraction followed by protein precipitation. Separation was performed in an Acquity UPLC® HSS C18 (150 ×2.1 mm, 1.8 µm), and the mobile phases were water and acetonitrile with 0.5% acetic acid. The total run time was 5.5 min. The method was linear from 100 to 2000 ng/mL, precise (maximum CV% of 7.5%), and accurate (98.3–115.4%). The average recovery was 70%. Blood hematocrit had a minimal impact on the assay. DBS samples were stable for 21 days at 4, 25, and 45 °C. A total of 40 paired samples of plasma, capillary DBS, and venous DBS were analyzed. Median 5-FU concentrations were 444.7, 637.0, and 499.7 ng/mL for plasma, capillary DBS, and venous DBS, respectively. Capillary and plasma concentrations were significantly correlated (r > 0.90), but there was a lack of agreement between the methods, as capillary DBS levels were on average 146% of plasma. Venous DBS corresponded to 110% of the measured plasma concentrations, with a strong correlation (r > 0.97) and agreement between the methods. Our study is the first to report the use of DBS samples to quantify 5-FU. Further studies are needed to establish whether capillary samples can replace plasma.
[Display omitted]
•5-Fluorouracil can be quantified in DBS using UHPLC–MS/MS.•Venous DBS can be used as alternative samples for 5-Fluorouracil TDM.•5-Fluorouracil is stable in DBS samples stored at 4, 25, and 45 °C for 21 days.</abstract><cop>England</cop><pub>Elsevier B.V</pub><pmid>37517245</pmid><doi>10.1016/j.jpba.2023.115539</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-0632-7955</orcidid></addata></record> |
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subjects | 5-Fluorouracil Dried blood spots Therapeutic drug monitoring UHPLC-MS/MS |
title | Evaluation of dried blood spots as an alternative sampling strategy for 5-fluorouracil monitoring: From method development to clinical application |
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