Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC-MS/MS assay and ultrafiltration method

被引:37
作者
Arellano, Cecile [1 ,2 ]
Gandia, Peggy [1 ,2 ]
Lafont, Thierry [1 ,2 ]
Jongejan, Rutchanna [3 ]
Chatelut, Etienne [1 ,2 ]
机构
[1] Univ Toulouse 3, Fac Pharm, F-31062 Toulouse 9, France
[2] Inst Claudius Regaud, Lab Pharmacocinet, EA4553, F-31052 Toulouse, France
[3] Univ Utrecht, NL-3508 TC Utrecht, Netherlands
来源
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES | 2012年 / 907卷
关键词
Imatinib; N-desmethyl imatinib; Unbound fraction; Ultrafiltration; UPLC-MS/MS; TANDEM MASS-SPECTROMETRY; ABL TYROSINE KINASE; MAIN METABOLITE CGP-74588; CHRONIC MYELOID-LEUKEMIA; PLASMA-PROTEIN BINDING; NONSPECIFIC-BINDING; POSITIVE CELLS; GIST PATIENTS; INHIBITOR; MESYLATE;
D O I
10.1016/j.jchromb.2012.09.007
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Imatinib is a small-molecule tyrosine kinase inhibitor with large inter-individual but low intra-individual pharmacokinetic variability with consistent concentration-efficacy and concentration-toxicity relationships. For these reasons imatinib therapeutic drug monitoring is based on total plasma concentrations. However, since a significant impact of unbound imatinib concentrations on clinical response and/or toxicity evaluation has been suggested, the quantification of free fraction of imatinib and its active metabolite are of interest for therapeutic monitoring. Hence a reliable method for both separation and assay of the free fraction is needed. Using plasma samples spiked with imatinib (from 1000 to 7500 ng/mL) and its metabolite (from 1000 to 2500 ng/mL), an ultrafiltration procedure and an UPLC assay which give reproductive values for unbound fractions of imatinib (mean 3.0 +/- 1.0%) and metabolite N-desmethyl imatinib (3.6 +/- 1.8%) have been developed. The validation of the analytical UPLC-MS/MS method associated to ultrafiltration for quantification of imatinib and N-desmethyl imatinib was reported. The LOQ was set at 10 ng/mL for imatinib and 20 ng/mL for N-desmethyl imatinib, intraday CV (%) ranged from 2.7 to 4.8% for imatinib and from 5.4 to 12.4% for N-desmethyl imatinib and interday CV (%) ranged from 5.6 to 6.5% for imatinib and from 5.4 to 16.1% for N-desmethyl imatinib. Methodological modifications were attempted to overcome non specific binding (NSB) on the ultrafiltration device. Two types of devices previously used for unbound determination of drugs were tested. Our results clearly showed that the methodology and the features of devices used for ultrafiltration could totally compromise the determination of unbound concentrations of a drug. (C) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:94 / 100
页数:7
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