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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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General Research Article

Simultaneous UPLC-MS/MS Determination of 6-mercaptopurine, 6-methylmercaptopurine and 6-thioguanine in Plasma: Application to the Pharmacokinetic Evaluation of Novel Dosage forms in Beagle Dogs

Author(s): Jiaqi Han, Shenghui Mei, Jiamin Xu, Dongjie Zhang, Siyao Jin, Zhigang Zhao* and Libo Zhao*

Volume 26, Issue 46, 2020

Page: [6013 - 6020] Pages: 8

DOI: 10.2174/1381612826999200820161343

Price: $65

Abstract

Background: 6-Mercaptopurine (6-MP) is widely used to treat pediatric acute lymphoblastic leukemia (ALL). Mini-tablets of 5 mg per tablet were developed for precision individual therapy for children and individuals with poor thiopurine S-methyltransferase (TPMT) or nucleoside diphophate-linked moiety X-type motif 15 (NUDT15) metabolism. This study investigated the pharmacokinetic profiles of mini-tablets and conventional tablets with an improved ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method.

Methods: After giving 8 healthy beagle dogs 50 mg 6-MP in different dosage forms, plasma samples collected at different time points were analyzed for pharmacokinetic evaluation. The samples were precipitated by methanol with 0.05% formic acid and separated on a Waters Atlantis T3 column (2.1 × 150 mm, 3 μm particles) using 0.1% formic acid in water and methanol at a flow rate of 0.4 mL/min in 4 min.

Results: This method showed good linearity, accuracy, precision and stability with a detection range of 5.0-500.0 ng/mL for 6-MP, 6-methylmercaptopurine (6-MMP) and 6-thioguanine (6-TG). The main parameters, half-life of apparent terminal disposition, maximum observed plasma concentration, total AUC extrapolated to infinity, AUC since initiation of the experiment, mean residence time, distribution volume and clearance were 1.62 ± 0.87 hours, 90.58 ± 60.43 ng/mL, 151.20 ± 94.18 ng·h/mL, 292.06 ± 184.02 ng·h2/mL, 1.90 ± 0.92 hours, 864.08 ± 538.52 L, and 432.75 ± 360.64 L/h for conventional tablets and 1.70 ± 1.10 hours, 84.15 ± 39.50 ng/mL, 147.70 ± 51.80 ng·h/mL, 300.92 ± 124.48 ng·h2/mL, 2.07 ± 0.50 hours, 756.90 ± 324.00 L, and 340.75 ± 125.81 L/h for minitablets, respectively. Paired t-tests showed no significant difference in any of the evaluated pharmacokinetic parameters between the two types tablets (P > 0.05).

Conclusion: Two dosage forms showed the same pharmacokinetic characteristics. This developing, novel formulation will help to provide a more accurate and optimal dosing regimen of 6-MP for humans in the future.

Keywords: Mercaptopurine, mini-tablets, pharmacokinetics, method development and validation, beagle dogs.

« Previous Next »
[1]
Bermejo San José F, Algaba A, López Durán S, et al. Mercaptopurine and inflammatory bowel disease: the other thiopurine. Rev Esp Enferm Dig 2017; 109(1): 10-6.
[PMID: 27809554]
[2]
de Oliveira BM, Valadares MT, Silva MR, Viana MB. Compliance with a protocol for acute lymphoblastic leukemia in childhood. Rev Bras Hematol Hemoter 2011; 33(3): 185-9.
[http://dx.doi.org/10.5581/1516-8484.20110051] [PMID: 23049293]
[3]
Schmiegelow K, Forestier E, Hellebostad M, et al. Nordic Society of Paediatric Haematology and Oncology. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia 2010; 24(2): 345-54.
[http://dx.doi.org/10.1038/leu.2009.251] [PMID: 20010622]
[4]
Milosevic G, Kotur N, Krstovski N, et al. Variants in TPMT, ITPA, ABCC4 and ABCB1 Genes As Predictors of 6-mercaptopurine Induced Toxicity in Children with Acute Lymphoblastic Leukemia. J Med Biochem 2018; 37(3): 320-7.
[http://dx.doi.org/10.1515/jomb-2017-0060] [PMID: 30598629]
[5]
Tanaka Y, Nakadate H, Kondoh K, Nakamura K, Koh K, Manabe A. Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia. Pharmacogenomics J 2018; 18(2): 275-80.
[http://dx.doi.org/10.1038/tpj.2017.12] [PMID: 28418010]
[6]
Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016; 48(4): 367-73.
[http://dx.doi.org/10.1038/ng.3508] [PMID: 26878724]
[7]
Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther 2004; 75(4): 274-81.
[http://dx.doi.org/10.1016/j.clpt.2003.12.001] [PMID: 15060506]
[8]
Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118(4): 705-13.
[http://dx.doi.org/10.1016/S0016-5085(00)70140-5] [PMID: 10734022]
[9]
Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 1994; 343(8907): 1188-90.
[http://dx.doi.org/10.1016/S0140-6736(94)92400-7] [PMID: 7909868]
[10]
Wojtuszkiewicz A, Barcelos A, Dubbelman B, et al. Assessment of mercaptopurine (6MP) metabolites and 6MP metabolic key-enzymes in childhood acute lymphoblastic leukemia. Nucleosides Nucleotides Nucleic Acids 2014; 33(4-6): 422-33.
[http://dx.doi.org/10.1080/15257770.2014.904519] [PMID: 24940700]
[11]
NCCN Guideline: Pediatric Acute Lymphoblastic Leukemia National Comprehensive Cancer Network. Available at:. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf2019.
[12]
Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther 2019; 105(5): 1095-105.
[http://dx.doi.org/10.1002/cpt.1304] [PMID: 30447069]
[13]
Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 2015; 33(11): 1235-42.
[http://dx.doi.org/10.1200/JCO.2014.59.4671] [PMID: 25624441]
[14]
Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv 2007; 4(1): 37-45.
[http://dx.doi.org/10.1517/17425247.4.1.37] [PMID: 17184161]
[15]
Hawwa AF, Millership JS, Collier PS, McElnay JC. Development and validation of an HPLC method for the rapid and simultaneous determination of 6-mercaptopurine and four of its metabolites in plasma and red blood cells. J Pharm Biomed Anal 2009; 49(2): 401-9.
[http://dx.doi.org/10.1016/j.jpba.2008.10.045] [PMID: 19095392]
[16]
Al-Ghobashy MA, Hassan SA, Abdelaziz DH, et al. Development and validation of LC-MS/MS assay for the simultaneous determination of methotrexate, 6-mercaptopurine and its active metabolite 6-thioguanine in plasma of children with acute lymphoblastic leukemia: Correlation with genetic polymorphism. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1038: 88-94.
[http://dx.doi.org/10.1016/j.jchromb.2016.10.035] [PMID: 27802917]
[17]
CLSI. Mass spectrometry in the clinical laboratory: general principles and guidance Available at: http://shop.clsi.org/c.1253739/site/Sample_pdf/C50A_sample.pdf2007
[18]
EMEA Committee for Medicinal Products for Human Use, Guideline on Bioanalytical Method Validation. Available at:. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf2011
[19]
FDA. Guidance for industry: bioanalytical method validationAvailable at: http://www.fda.gov/ucm/groups/fdagov-public/@ fdagov-drugsgen/documents/document/ucm368107.pdf2013
[20]
Dervieux T, Meyer G, Barham R, et al. Liquid chromatographytandem mass spectrometry analysis of erythrocyte thiopurine nucleotides and effect of thiopurine methyltransferase gene variants on these metabolites in patients receiving azathioprine/6- mercaptopurine therapy. Clin Chem 2005; 51(11): 2074-84..
[http://dx.doi.org/10.1373/clinchem.2005.050831] [PMID: 16166171]
[21]
Kirchherr H, Shipkova M, von Ahsen N. Improved method for therapeutic drug monitoring of 6-thioguanine nucleotides and 6-methylmercaptopurine in whole-blood by LC/MSMS using isotope-labeled internal standards. Ther Drug Monit 2013; 35(3): 313-21.
[http://dx.doi.org/10.1097/FTD.0b013e318283ed5d] [PMID: 23666567]
[22]
Mei S, Li X, Gong X, et al. LC-MS/MS analysis of erythrocyte thiopurine nucleotides and their association with genetic variants in patients with neuromyelitis optica spectrum disorders taking azathioprine. Ther Drug Monit 2017; 39(1): 5-12.
[http://dx.doi.org/10.1097/FTD.0000000000000362] [PMID: 27941536]
[23]
Mei S, Li X, Gong X, et al. Comparison of 6-mercaptopurine with 6-thioguanine for the analysis of thiopurine S-methyltransferase activity in human erythrocyte by LC-MS/MS. Biomed Chromatogr 2017; 31(9): 31.
[http://dx.doi.org/10.1002/bmc.3959] [PMID: 28212467]
[24]
Supandi S, Harahap Y, Harmita H, Andalusia R. Quantification of 6-mercaptopurine and its metabolites in patients with acute lympoblastic leukemia using dried blood spots and UPLC-MS/MS. Sci Pharm 2018; 86(2): 86.
[http://dx.doi.org/10.3390/scipharm86020018] [PMID: 29693618]
[25]
Zimm S, Collins JM, Riccardi R, et al. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 1983; 308(17): 1005-9.
[http://dx.doi.org/10.1056/NEJM198304283081705] [PMID: 6572786]
[26]
Tiphaine Ade B, Hjalgrim LL, Nersting J, et al. Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children. Eur J Pharm Sci 2016; 83: 1-7.
[http://dx.doi.org/10.1016/j.ejps.2015.12.002] [PMID: 26657824]
[27]
Tolbert JA, Bai S, Abdel-Rahman SM, et al. Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2017; 64(8)
[http://dx.doi.org/10.1002/pbc.26465] [PMID: 28295989]
[28]
Saiz-Rodríguez M, Ochoa D, Belmonte C, et al. Influence of thiopurine S-methyltransferase polymorphisms in mercaptopurine pharmacokinetics in healthy volunteers. Basic Clin Pharmacol Toxicol 2019; 124(4): 449-55.
[http://dx.doi.org/10.1111/bcpt.13153] [PMID: 30346660]
[29]
Zaza G, Cheok M, Krynetskaia N, et al. Thiopurine pathway. Pharmacogenet Genomics 2010; 20(9): 573-4.
[http://dx.doi.org/10.1097/FPC.0b013e328334338f] [PMID: 19952870]
[30]
Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 2019; 570(7762): 462-7.
[http://dx.doi.org/10.1038/s41586-019-1291-3] [PMID: 31158845]
[31]
Wen Y, Jin R, Chen H. Interactions between gut microbiota and acute childhood leukemia. Front Microbiol 2019; 10: 1300.
[http://dx.doi.org/10.3389/fmicb.2019.01300] [PMID: 31275258]

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