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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

[ Vol. 26 , Issue. 46 ]

Author(s):

Jiaqi Han, Shenghui Mei, Jiamin Xu, Dongjie Zhang, Siyao Jin, Zhigang Zhao* and Libo Zhao*   Pages 6013 - 6020 ( 8 )

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.

Affiliation:

Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Capital Medical University, Beijing100050, Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Capital Medical University, Beijing100050, Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045



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