SAFE USE OF FLUOROPYRIMIDINES IN ONCOLOGY:  DEVELOPMENT OF A METHOD FOR THE DETERMINATION OF PLASMA URACIL AND DIHYDROURACIL LEVELS BY UHPLC-MS-MS AND SCREENING FOR DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY

Farida Bouchenak; Nardjess Rim Laoufi; Khaled Sobhi; Djamal Sadouki; Mohammed Hazi; Samir Adjmi; Kamel Mansouri; Kamel Bouzid

doi:10.4314/jfas.1320

Authors

Farida Bouchenak Toxicology Laboratory, Central Army Hospital Dr. Mohamed Seghir Nekkache, Algeria
Nardjess Rim Laoufi Toxicology Laboratory, Central Army Hospital Dr. Mohamed Seghir Nekkache, Algeria
Khaled Sobhi Toxicology Laboratory, Central Army Hospital Dr. Mohamed Seghir Nekkache, Algeria
Djamal Sadouki Toxicology Laboratory, Central Army Hospital Dr. Mohamed Seghir Nekkache, Algeria
Mohammed Hazi Medical Oncology. Central Army Hospital Dr. Mohamed Seghir Nekkache, Algeria
Samir Adjmi Medical Oncology. Central Army Hospital Dr. Mohamed Seghir Nekkache, Algeria
Kamel Mansouri Pharmacology Laboratory. Faculty of Pharmacy. University of Algiers I
Kamel Bouzid Medical Oncology. Centre Pierre Marie Curie (CPMC), Algeria

DOI:

https://doi.org/10.4314/jfas.1320

Keywords:

Uracil, Screening, ; DPD Deficiency., Fluoropyrimidines

Abstract

5-Fluorouracil (5-FU) is a widely used drug in oncology. It can cause toxicity, especially in the case of Dihydropyrimidine Dehydrogenase (DPD) deficiency. An enzyme responsible for the inactivation of more than 80% of the 5-FU dose and for the transformation of uracil (U) into dihydrouracile (UH₂). A sensitive method is needed to screen for DPD deficiency by determination of U level, as recommended by the European Medicine Agency (EMA). Separation was performed by an UHPLC on a C₁₈ column and a tandem mass spectrometer performed the detection of U and UH₂. The method’s performance was validated according to ICH M10 recommendations. The validated method was used to screen for DPD deficiency in fifty-seven hospitalized patients. None of the patients showed DPD deficiency based on the U-rate instead of the metabolic ratio UH₂/U (7.08%) which might be a more sensitive tool for this screening.

Downloads

Download data is not yet available.

References

Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clinical Pharmacology & Therapeutics., 2018, 103(2):210‑6. doi: https://doi.org/10.1002/cpt.911

Tsalic M, Bar-Sela G, Beny A, Visel B, Haim N. Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. Am J Clin Oncol., 2003, 26(1):103‑6.

doi: https://doi.org/10.1097/01.coc.0000017526.55135.6d

Meta-Analysis Group In Cancer, Lévy E, Piedbois P, Buyse M, Pignon JP, Rougier P, et al. Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol., 1998, 16(11) :3537‑41.

doi: https://doi.org/10.1200/jco.1998.16.11.3537

Marques RP, Duarte GS, Sterrantino C, Pais HL, Quintela A, Martins AP, et al. Triplet (FOLFOXIRI) versus doublet (FOLFOX or FOLFIRI) backbone chemotherapy as first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol., 2017, 118:54‑62. doi: https://doi.org/10.1016/j.critrevonc.2017.08.006

Johnson MR, Wang K, Tillmanns S, Albin N, Diasio RB. Structural organization of the human dihydropyrimidine dehydrogenase gene. Cancer Res. 1997, 1;57(9):1660-3.

Miller E. The metabolism and pharmacology of 5-fluorouracil. Journal of Surgical Oncology., 1971, 3(3):309‑15. doi: https://doi.org/10.1002/jso.2930030311

Heggie GD, Sommadossi JP, Cross DS, Huster WJ, Diasio RB. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res., 1987, 47(8):2203‑6.

Allegra CJ. Dihydropyrimidine dehydrogenase activity: prognostic partner of 5-fluorouracil? Clin Cancer Res., 1999, 5(8) :1947‑9.

Lemaitre F, Goirand F, Launay M, Chatelut E, Boyer JC, Evrard A, et al. Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer. Bulletin du Cancer., 2018, 105(9):790‑803.

doi: https://dx.doi.org/10.1016/j.bulcan.2018.06.008

Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing. Clinical Pharmacology & Therapeutics., 2013, 94(6):640‑5. doi: https://doi.org/10.1038/clpt.2013.172

Diasio RB. The role of dihydropyrimidine dehydrogenase (DPD) modulation in 5-FU pharmacology. Oncology (Williston Park)., 1998,12(10 Suppl 7):23-7.

Lemaire L, Malet-Martino MC, Longo S, Martino R, de Forni M, Carton M. Fluoroacetaldehyde as cardiotoxic impurity in fluorouracil (Roche). Lancet., 1991, 337(8740):560. doi: https://doi.org/10.1016/0140-6736(91)91353-v

Boisdron-Celle M, Morel A, Gamelin E. Déficits en dihydropyrimidine déshydrogénase et toxicité aux fluoropyrimidines. Annales de biologie clinique., 2010;(1):27‑32.

doi: https://www.jle.com/10.1684/abc.2010.0394

Ezzeldin H, Diasio R. Dihydropyrimidine Dehydrogenase Deficiency, a Pharmacogenetic Syndrome Associated with Potentially Life-Threatening Toxicity Following 5-Fluorouracil Administration. Clinical Colorectal Cancer., 2004, 4(3):181‑9.

doi: https://doi.org/10.3816/ccc.2004.n.018

Harris BE, Song R, Soong SJ, Diasio RB. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res., 1990, 50(1):197‑201.

Paolo AD, Danesi R, Falcone A, Cionini L, Vannozzi F, Masi G, et al. Relationship between 5-fluorouracil disposition, toxicity and dihydropy rimidine dehydrogenase activity in cancer patients. Ann Oncol., 2001,12(9):1301‑6. doi: https://doi.org/10.1023/a:1012294617392

Meulendijks D, Henricks LM, Jacobs BAW, Aliev A, Deenen MJ, de Vries N, et al. Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. Br J Cancer., 2017, 116(11):1415‑24.

doi: https://doi.org/10.1038/bjc.2017.94

Loriot MA, Ciccolini J, Thomas F, Barin-Le-Guellec C, Royer B, Milano G, et al. Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx. Bulletin du Cancer., 2018, 105(4):397‑407.

doi: https://doi.org/10.1016/j.bulcan.2018.02.001

van Staveren MC, Guchelaar HJ, van Kuilenburg ABP, Gelderblom H, Maring JG. Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmacogenomics J., 2013, 13(5):389‑95. doi: https://doi.org/10.1038/tpj.2013.25

Screening for dihydropyrimidine dehydrogenase deficiency to decrease the risk of severe toxicities related to fluoropyrimidines (5-fluorouracil or capecitabine). Haute Autorité de Santé. 2018.

https://www.has-sante.fr/jcms/c_2891090/fr/methodes-de-recherche-d-un-deficit-en-dihydropyrimidine-deshydrogenase-visant-a-prevenir-certaines-toxicites-severes-associees-aux-traitements-incluant-une-fluoropyrimidine-5-fluorouracile-ou-capecitabine

Meulendijks D, Cats A, Beijnen JH, Schellens JHM. Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity – Ready for clinical practice? Cancer Treatment Reviews., 2016, 50:23‑34.

doi: https://doi.org/10.1016/j.ctrv.2016.08.002

Boisdron-Celle M, Remaud G, Traore S, Poirier AL, Gamelin L, Morel A, et al. 5-Fluorouracil-related severe toxicity: A comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. Cancer Letters., 2007, 249(2):271‑82. doi: https://doi.org/10.1016/j.canlet.2006.09.006

Capitain O, Seegers V, Metges JP, Faroux R, Stampfli C, Ferec M, et al. Comparison of 4 Screening Methods for Detecting Fluoropyrimidine Toxicity Risk: Identification of the Most Effective, Cost-Efficient Method to Save Lives. Dose Response., 2020, 18(3):1559325820951367. doi: https://doi.org/10.1177/1559325820951367

Marin C, Krache A, Palmaro C, Lucas M, Hilaire V, Ugdonne R, et al. A Simple and Rapid UPLC‐UV Method for Detecting DPD Deficiency in Patients With Cancer. Clin Transl Sci., 2020, 13(4):761‑8. doi: https://doi.org/10.1111%2Fcts.12762

Remaud G, Boisdron-Celle M, Hameline C, Morel A, Gamelin E. An accurate dihydrouracil/uracil determination using improved high performance liquid chromatography method for preventing fluoropyrimidines-related toxicity in clinical practice. J Chromatogr B Analyt Technol Biomed Life Sci., 2005, 823(2):98‑107.

doi: https://doi.org/10.1016/j.jchromb.2005.05.044

Svobaite R, Solassol I, Pinguet F, Ivanauskas L, Brès J, Bressolle FMM. HPLC with UV or mass spectrometric detection for quantifying endogenous uracil and dihydrouracil in human plasma. Clin Chem., 2008, 54(9):1463‑72. doi: https://doi.org/10.1373/clinchem.2007.102251

Saif Eddine Gamaoun E, Saad Saguem. Extraction sur phase solide et analyses par HPLC du 5-fluoro-uracile plasmatique. EM-Consulte,. 2005, 8(9‑10):1688‑93.

doi: https://doi.org/10.1016/j.crci.2005.04.002

Galarza AFA, Linden R, Antunes MV, Hahn RZ, Raymundo S, da Silva ACC, et al. Endogenous plasma and salivary uracil to dihydrouracil ratios and DPYD genotyping as predictors of severe fluoropyrimidine toxicity in patients with gastrointestinal malignancies. Clin Biochem., 2016, 49(16‑17):1221‑6.

doi: https://doi.org/10.1016/j.clinbiochem.2016.07.004

Büchel B, Rhyn P, Schürch S, Bühr C, Amstutz U, Largiadèr CR. LC-MS/MS method for simultaneous analysis of uracil, 5,6-dihydrouracil, 5-fluorouracil and 5-fluoro-5,6-dihydrouracil in human plasma for therapeutic drug monitoring and toxicity prediction in cancer patients. Biomed Chromatogr., 2013, 27(1):7‑16. doi: https://doi.org/10.1002/bmc.2741

Coudoré F, Roche D, Lefeuvre S, Faussot D, Billaud EM, Loriot MA, et al. Validation of an ultra-high performance liquid chromatography tandem mass spectrometric method for quantifying uracil and 5,6-dihydrouracil in human plasma. J Chromatogr Sci., 2012, 50(10):877‑84. doi: https://doi.org/10.1093/chromsci/bms085

Shiraiwa K, Suzuki Y, Uchida H, Iwashita Y, Tanaka R, Iwao M, et al. Simultaneous quantification method for 5-FU, uracil, and tegafur using UPLC-MS/MS and clinical application in monitoring UFT/LV combination therapy after hepatectomy. Sci Rep., 2021, 11(1):31-32. doi: https://doi.org/10.1038%2Fs41598-021-82908-8

Jiang H, Jiang J, Hu P, Hu Y. Measurement of endogenous uracil and dihydrouracil in plasma and urine of normal subjects by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci., 2002, 769(1):169‑76.

doi: https://doi.org/10.1016/s1570-0232(02)00009-0

Neto OV, Raymundo S, Franzoi MA, do Carmo Artmann A, Tegner M, Müller VV, et al. DPD functional tests in plasma, fresh saliva and dried saliva samples as predictors of 5-fluorouracil exposure and occurrence of drug-related severe toxicity. Clin Biochem., 2018, 56:18‑25. doi: https://doi.org/10.1016/j.clinbiochem.2018.04.001

EMA. ICH M10 on bioanalytical method validation [Internet]. European Medicines Agency., 2019. https://www.ema.europa.eu/en/ich-m10-bioanalytical-method-validation

Khennoufa A, Bechki L, Lanez T, Lanez E, Zegheb N. Spectrophotometric, voltammetric and molecular docking studies of binding interaction of N-ferrocenylmethylnitroanilines with bovine serum albumin. Journal of Molecular Structure, 2021, 129052, doi: https://doi.org/10.1016/j.molstruc.2020.129052

Benamara H, Lanez T, Lanez E. .BSA-binding studies of 2- and 4-ferrocenylbenzonitrile: voltammetric, spectroscopic and molecular docking investigations. Journal of Electrochemical Science and Engineering, 2020, 10(4), 335-346, doi: https://doi.org/10.5599/jese.861

Robin T, Saint-Marcoux F, Toinon D, Tafzi N, Marquet P, El Balkhi S. Automatic quantification of uracil and dihydrouracil in plasma. Journal of Chromatography B - Analytical Technologies in the Biomedical and Life Sciences., 2020, 1142:122038-.

doi: https://doi.org/10.1016/j.jchromb.2020.122038

Garg MB, Sevester JC, Sakoff JA, Ackland SP. Simple liquid chromatographic method for the determination of uracil and dihydrouracil plasma levels: a potential pretreatment predictor of 5-fluorouracil toxicity. J Chromatogr B Analyt Technol Biomed Life Sci., 2002, 774(2):223‑30. doi: https://doi.org/10.1016/s1570-0232(02)00239-8

Jacobs BAW, Rosing H, de Vries N, Meulendijks D, Henricks LM, Schellens JHM, et al. Development and validation of a rapid and sensitive UPLC–MS/MS method for determination of uracil and dihydrouracil in human plasma. Journal of Pharmaceutical and Biomedical Analysis., 2016, 126:75‑82. doi: https://doi.org/10.1016/j.jpba.2016.04.039

Temmink OH, de Bruin M, Laan AC, Turksma AW, Cricca S, Masterson AJ, et al. The role of thymidine phosphorylase and uridine phosphorylase in fluoropyrimidine metabolism in peripheral blood mononuclear cells. Int J Biochem Cell Biol., 2006, 38(10):1759‑65.

doi: https://doi.org/10.1016/j.biocel.2006.04.007

Kuilenburg ABPV, Lenthe H van, Blom MJ, Mul EPJ, Gennip AHV. Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the detection of partly deficient patients. Br J Cancer., 1999, 79(3‑4):620‑6. –247.

doi: https://doi.org/10.1038%2Fsj.bjc.6690097