Cytarabine determination from urine for Toxicokinetic and Excretion studies by High- Performance Liquid Chromatography-Tandem Mass Spectrometry

Cytarabine (Cyt) (also known as cytosine arabinoside (ara-C)) used in the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL). CYT applied in high doses for treatment can cause renal failure. Monitoring excreted urine drug levels can help kidney failure. For this reason, a method was developed and validated by HPLC-MSMS for urine CYT analysis, which is not included in the literature. In this study, a liquid chromatography (HPLC) with triple quadrupole Mass Spectrometric (MS/MS) method developed for the determination of Cyt from urine for toxicokinetic evaluation. Positive MRM mode selected for the quantification of Cyt. The product and major fragment ion for Cyt 244.0 > 112.0 m/z, for IS 198.0 > 152.0 m/z. The optimal MS parameters for Cyt and IS are as follows Fragmentor 80 V, 70 V, Collision energy, 6, 9 respectively. A novel simple, high-throughput and highly sensitive HPLC-MS/MS method was successfully developed and validated for the determination of Cyt from urine. The developed method has a simple one-step extraction method and a short run time (2.0 minutes) for analysis. The proposed method could be practical and reliable for excretion and toxicokinetic studies and as well as the Therapeutic Drug Monitoring study in humans without an invasive route for Cyt.

Keywords:

Cytarabine therapeutic drug monitoring, toxicokinetics, mass spectrometry,

PDF

___

1. Burstein HJ, Krilov L, Aragon-Ching JB, Baxter NN, Chiorean EG at al. Clinical cancer advances 2017: annual report on progress against cancer from the american society of clinical oncology. Journal of Clinical Oncology 2017; 35 (12): 1341-1367. doi: 10.1200/JCO.2016.71.5292
2. Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM et al. Annual report to the nation on the status of cancer, part 1: national cancer statistics. Cancer 2018; 124 (13): 2785-2800. doi: 10.1002/cncr.31551
3. Lamba JK. Genetic factors influencing cytarabine therapy. Pharmacogenomics 2009; 10 (10): 1657-74. doi: 10.2217/pgs.09.118
4. Hamada A, Kawaguchi T, Nakano M. Clinical pharmacokinetics of cytarabine formulations. Clinical Pharmacokinetics 2002; 41 (10): 705-18. doi: 10.2165/00003088-200241100-00002
5. Löwenberg B, Downing JR, Burnett A. Acute myeloid leukemia. The New England Journal of Medicine 1999; 341: 1051-1062 doi: 10.1056/NEJM199909303411407
6. Löwenberg B, Pabst T, Vellenga E, Van Putten W, Schouten HC. Cytarabine dose for acute myeloid leukemia. The New England Journal of Medicine 2011; 364: 1027-1036 doi: 10.1056/NEJMoa1010222
7. Dotson JL, Jamil MO. Successful treatment of cytarabine-related neurotoxicity with corticosteroids, a case series. International Journal of Hematology 2018; 108 (5): 554-557. doi: 10.1007/s12185-018-2485-4
8. Mori T, Yamazaki R, Nakazato T, Aisa Y, Enoki S, et al. Excretion of cytosine arabinoside in saliva after its administration at high doses. Anticancer Drugs 2006; 17 (5): 597-8. doi: 10.1097/00001813-200606000-00015
9. Burk M, Volmer M, Fartash K, Schneider W. Ion-pair liquid chromatography of cytarabine and uracil-arabinoside in human plasma. Arzneimittelforschung 1995; 45 (5): 616-9.
10. Hsieh Y, Duncan CJ. An ion-pairing liquid chromatography/tandem mass spectrometric method for the determination of cytarabine in mouse plasma. Rapid Communications in Mass Spectrometry 2007; 21 (4): 573-8. doi: 10.1002/rcm.2877
11. Hsieh Y, Duncan CJ, Liu M. A mixed-mode liquid chromatography-tandem mass spectrometric method for the determination of cytarabine in mouse plasma. Journal of Chromatography B 2007; 854 (1-2): 8-12. doi: 10.1016/j.jchromb.2007.03.034
12. Hsieh Y, Duncan CJ, Brisson JM. Porous graphitic carbon chromatography/tandem mass spectrometric determination of cytarabine in mouse plasma. Rapid Communications Mass Spectrometry 2007; 21 (5): 629-34. doi: 10.1002/rcm.2879
13. Sun Y, Sun J, Wen B, Shi S, Xu Y. High-performance liquid chromatography/tandem mass spectrometry method for the simultaneous determination of cytarabine and its valyl prodrug valcytarabine in rat plasma. Journal of Chromatography B 2008; 870 (1): 121-5. doi: 10.1016/j.jchromb.2008.05.033
14. Mistiran AF, Dzarr AA, Gan SH. HPLC method development and validation for simultaneous detection of Arabinoside-C and doxorubicin. Toxicology Mechanisms and Methods, 2010; 20 (8): 472-81. doi: 10.3109/15376516.2010.503246
15. Hilhorst MJ, Hendriks G, Van Hout MW, Sillén H, Van de Merbel NC. HPLC-MS/MS method for the determination of cytarabine in human plasma. Bioanalysis 2011; 3 (14): 1603-11. doi: 10.4155/bio.11.140
16. Feldman EJ, Kolitz JE, Trang JM, Liboiron BD, Swenson CE. Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine: daunorubicin, in patients with advanced leukemia. Leukemia Research 2012; 36 (10): 1283-9. doi: 10.1016/j.leukres.2012.07.006
17. Phillips CL, Lane A, Gerbing RB, Alonzo TA, Wilkey A. Genomic variants of cytarabine sensitivity associated with treatment-related mortality in pediatric aml: a report from the children’s oncology group. Clinical Cancer Research 2020; 26 (12): 2891-2897. doi: 10.1158/1078-0432.CCR-19-3117
18. Guideline on bioanalytical method validation, 1 July 2011, EMEA / CHMP / EWP / 192217.