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Current Pharmaceutical Analysis


ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

Simultaneous Determination of Imatinib and N-Desmethyl Imatinib in Rat Plasma and Tissues Using LC-MS/MS

Author(s): Zhi Rao, Bo-xia Li, Yong-Wen Jin, Wen-Kou, Yan-rong Ma, Guo-qiang Zhang, Fan Zhang, Yan Zhou and Xin-an Wu*

Volume 15, Issue 2, 2019

Page: [121 - 129] Pages: 9

DOI: 10.2174/1573412913666170821124952

Price: $65


Background: Imatinib (IM) is a chemotherapy medication metabolized by CYP3A4 to Ndesmethyl imatinib (NDI), which shows similar pharmacologic activity to the parent drug. Although methods for determination of IM and/or NDI have been developed extensively, only few observations have been addressed to simultaneously determine IM and NDI in biological tissues such as liver, kidney, heart, brain and bone marrow.

Methods: A validated LC-MS/MS method was developed for the quantitative determination of imatinib (IM) and N-desmethyl imatinib (NDI) from rat plasma, bone marrow, brain, heart, liver and kidney. The plasma samples were prepared by protein precipitation, and then the separation of the analytes was achieved using an Agilent Zorbax Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with gradient elution running water (A) and methanol (B). Mass spectrometric detection was achieved by a triplequadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode.

Results: This method was used to investigate the pharmacokinetics and the tissue distributions in rats following oral administration of 25 mg/kg of IM. The pharmacokinetic profiles suggested that IM and NDI are disappeared faster in rats than human, and the tissue distribution results showed that IM and NDI had good tissue penetration and distribution, except for the brain. This is the first report about the large penetrations of IM and NDI in rat bone marrow.

Conclusion: The method demonstrated good sensitivity, accuracy, precision and recovery in assays of IM and NDI in rats. The described assay was successfully applied for the evaluation of pharmacokinetics and distribution in the brain, heart, liver, kidney and bone marrow of IM and NDI after a single oral administration of IM to rats.

Keywords: Imatinib, N-desmethyl imtinib, LC-MS/MS, pharmacokinetics, tissue distributions, bone marrow, Imatinib-d8.

Graphical Abstract
Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.; Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, S.; Ohno-Jones, S.; Sawyers, C.L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. Eng. J. Med., 2001, 344, 1031-1037.
Peggs, K.; Mackinnon, S. Imatinib mesylate—the new gold standard for treatment of chronic myeloid leukemia. Eng. J. Med., 2003, 348, 1048-1050.
Giles, F.J.; O’Dwyer, M.; Swords, R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia, 2009, 24, 1698-1707.
Tribelli, M.; Medeot, M. Cardiotoxicity of imatinib: at the heart of the problem. Leukemia . Res., 2011, 35, 36-37.
Arellano, C.; Gandia, P.; Lafont, T.; Jongejan, R.; Chatelut, E. Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC-MS/MS assay and ultrafiltration method. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 907, 94-100.
Schleyer, E.; Pursche, S.; Köhne, C.H.; Schuler, U.; Renner, U.; Gschaidmeier, H.; Freiberg-Righter, J.; Leopold, T.; Jenke, A.; Bonin, M.; Bergemann, T.; le Coutre, P.; Gruner, M.; Bornhäuser, M.; Ottmann, O.G.; Ehninger, G. Liquid chromatographic method for detection and quantitation of STI-571 and its main metabolite N-desmethyl-STI in plasma, urine, cerebrospinal fluid, culture medium and cell preparations. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2004, 799, 23-36.
Tuntiyasawasdikul, S.; Sripanidkulchai, B. LC-MS for determination of three methoxyflavones from kaempferia parviflora in rat plasma and application to pharmacokinetic study. Curr. Pharm. Anal., 2016, 12, 371-378.
Park, J.W.; Hoang, N.H.; Huong, N.L. Analysis of ursodeaxycholic acid using ultra-performance liquid chromatography with tandem mass spectrometry. Curr. Pharm. Anal., 2016, 12, 185-191.
Li, Q.Y.; Yang, Y.; Shi, G.B.; Zhang, J.; Li, G.Q.; Sui, Y.; Tang, Y.B.; Gu, J.K. Simultaneous quantification of simvastatin and simvastatin acid in human plasma with a highly sensitive LC-ESI-MS/MS method: application to a pharmacokinetic study in healthy Chinese volunteers with a fixed dose of simvastatin and extended-release niacin combination tablet. Curr. Pharm. Anal., 2016, 12, 96-106.
Lee, S.H.; Kim, H.J.; Kim, S.H.; Park, Y.S.; Kang, M.A.; Kim, D.W.; Kang, J.S. Quantification of imidapril in human plasma using the LC-MS/MS method for bioequivalence and pharmacokinetic studies. Curr. Pharm. Anal., 2016, 12, 107-113.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry, Analytical Procedures and Methods Validation for Drugs and Biologics. 2014: 1-14.
Rao, Z.; Ma, Y.R.; Qin, H.Y.; Wang, Y.F.; Wei, Y.H.; Zhou, Y.; Zhang, G.Q.; Wang, X.D.; Wu, X.A. Development of a LC-MS/MS method for simultaneous determination of metoprolol and its metabolites, α-hydroxymetoprolol and O-desmethylmetoprolol, in rat plasma: application to the herb-drug interaction study of metoprolol and breviscapine. Biomed. Chromatogr., 2015, 29, 1453-1460.
Zhang, Y.; Qiang, S.; Yu, Z.; Zhang, W.; Xu, Z.; Yang, L.; Wen, A.; Hang, T. LC-MS/MS determination of imatinib and N-desmethyl imatinib in human plasma. J. Chromatogr. Sci., 2014, 52, 344-350.
Soo, G.W.; Law, J.H.; Kan, E.; Tan, S.Y.; Lim, W.Y.; Chay, G.; Buhari, N.I.; Segarra, I. Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice. Anticancer Drugs, 2010, 21, 695-703.

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