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.
[PMID: 27809554]
[http://dx.doi.org/10.5581/1516-8484.20110051] [PMID: 23049293]
[http://dx.doi.org/10.1038/leu.2009.251] [PMID: 20010622]
[http://dx.doi.org/10.1515/jomb-2017-0060] [PMID: 30598629]
[http://dx.doi.org/10.1038/tpj.2017.12] [PMID: 28418010]
[http://dx.doi.org/10.1038/ng.3508] [PMID: 26878724]
[http://dx.doi.org/10.1016/j.clpt.2003.12.001] [PMID: 15060506]
[http://dx.doi.org/10.1016/S0016-5085(00)70140-5] [PMID: 10734022]
[http://dx.doi.org/10.1016/S0140-6736(94)92400-7] [PMID: 7909868]
[http://dx.doi.org/10.1080/15257770.2014.904519] [PMID: 24940700]
[http://dx.doi.org/10.1002/cpt.1304] [PMID: 30447069]
[http://dx.doi.org/10.1200/JCO.2014.59.4671] [PMID: 25624441]
[http://dx.doi.org/10.1517/17425247.4.1.37] [PMID: 17184161]
[http://dx.doi.org/10.1016/j.jpba.2008.10.045] [PMID: 19095392]
[http://dx.doi.org/10.1016/j.jchromb.2016.10.035] [PMID: 27802917]
[http://dx.doi.org/10.1373/clinchem.2005.050831] [PMID: 16166171]
[http://dx.doi.org/10.1097/FTD.0b013e318283ed5d] [PMID: 23666567]
[http://dx.doi.org/10.1097/FTD.0000000000000362] [PMID: 27941536]
[http://dx.doi.org/10.1002/bmc.3959] [PMID: 28212467]
[http://dx.doi.org/10.3390/scipharm86020018] [PMID: 29693618]
[http://dx.doi.org/10.1056/NEJM198304283081705] [PMID: 6572786]
[http://dx.doi.org/10.1016/j.ejps.2015.12.002] [PMID: 26657824]
[http://dx.doi.org/10.1002/pbc.26465] [PMID: 28295989]
[http://dx.doi.org/10.1111/bcpt.13153] [PMID: 30346660]
[http://dx.doi.org/10.1097/FPC.0b013e328334338f] [PMID: 19952870]
[http://dx.doi.org/10.1038/s41586-019-1291-3] [PMID: 31158845]
[http://dx.doi.org/10.3389/fmicb.2019.01300] [PMID: 31275258]