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Etienne Chatelut - One of the best experts on this subject based on the ideXlab platform.
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should therapeutic drug monitoring of the unbound fraction of Imatinib and its main active metabolite n desmethyl Imatinib be developed
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Peggy Gandia, Laurence Malard, Cecile Arellano, Françoise Huguet, Thierry Lafont, Etienne ChatelutAbstract:Purpose The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for Imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both Imatinib and its main active metabolite (N-desmethylImatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of Imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations. Patients and methods The quantification of unbound fraction of Imatinib and N-desmethyl-Imatinib was performed using plasma ultrafiltration coupled with LC‐MS/ MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients. Results The mean unbound fractions of Imatinib and N-desmethyl-Imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for Imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for Imatinib and 34 % for N-desmethylImatinib. No correlation was observed between these measured individual Imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-Imatinib/Imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with interindividual variabilities of 71 and 86 %, respectively. Conclusion The large inter-individual variability for the unbound fraction of both Imatinib and N-desmethyl-Imatinib warrants further evaluation of the pharmacokinetic‐pharmacodynamic relationship as a potential relevant marker of Imatinib therapeutic outcomes.
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determination of unbound fraction of Imatinib and n desmethyl Imatinib validation of an uplc ms ms assay and ultrafiltration method
Analytical Abstracts, 2012Co-Authors: Cecile Arellano, Peggy Gandia, Rutchanna Jongejan, Thierry Lafont, Etienne ChatelutAbstract: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.
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Determination of unbound fraction of Imatinib and N-desmethyl Imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method
Journal of Chromatography B, 2012Co-Authors: Cecile Arellano, Peggy Gandia, Rutchanna Jongejan, Thierry Lafont, Etienne ChatelutAbstract:Abstract 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.
Joan Sayós - One of the best experts on this subject based on the ideXlab platform.
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silencing of adaptor protein sh3bp2 reduces kit pdgfra receptors expression and impairs gastrointestinal stromal tumors growth
Molecular Oncology, 2018Co-Authors: Eva Serranocandelas, Paulo Rodrigues, Sarah Bazzocco, Irati Macaya, Joaquín Arribas, César Serrano, Erola Ainsuaenrich, Arnau Navinesferrer, Alfonso Garciavalverde, Joan SayósAbstract:Gastrointestinal stromal tumors (GISTs) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GISTs contain oncogenic KIT (85%) or PDGFRA (5%) receptors. The kinase inhibitor Imatinib mesylate is the preferential treatment for these tumors; however, the development of drug resistance has highlighted the need for novel therapeutic strategies. Recently, we reported that the adaptor molecule SH3 Binding Protein 2 (SH3BP2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH3BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in Imatinib-sensitive and Imatinib-resistant GIST cells. The microphthalmia-associated transcription factor (MITF), involved in KIT expression in mast cells and melanocytes, is expressed in GISTs. Interestingly, MITF is reduced after SH3BP2 silencing. Importantly, reconstitution of both SH3BP2 and MITF restores cell viability. Furthermore, SH3BP2 silencing significantly reduces cell migration and tumor growth of Imatinib-sensitive and Imatinib-resistant cells in vivo. Altogether, SH3BP2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in Imatinib-sensitive and Imatinib-resistant GISTs.
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Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth.
Molecular oncology, 2018Co-Authors: Eva Serrano-candelas, Erola Ainsua-enrich, Arnau Navinés-ferrer, Paulo Rodrigues, Alfonso García-valverde, Sarah Bazzocco, Irati Macaya, Joaquín Arribas, César Serrano, Joan SayósAbstract:Gastrointestinal stromal tumors (GISTs) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GISTs contain oncogenic KIT (85%) or PDGFRA (5%) receptors. The kinase inhibitor Imatinib mesylate is the preferential treatment for these tumors; however, the development of drug resistance has highlighted the need for novel therapeutic strategies. Recently, we reported that the adaptor molecule SH3 Binding Protein 2 (SH3BP2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH3BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in Imatinib-sensitive and Imatinib-resistant GIST cells. The microphthalmia-associated transcription factor (MITF), involved in KIT expression in mast cells and melanocytes, is expressed in GISTs. Interestingly, MITF is reduced after SH3BP2 silencing. Importantly, reconstitution of both SH3BP2 and MITF restores cell viability. Furthermore, SH3BP2 silencing significantly reduces cell migration and tumor growth of Imatinib-sensitive and Imatinib-resistant cells in vivo. Altogether, SH3BP2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in Imatinib-sensitive and Imatinib-resistant GISTs.
Peggy Gandia - One of the best experts on this subject based on the ideXlab platform.
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should therapeutic drug monitoring of the unbound fraction of Imatinib and its main active metabolite n desmethyl Imatinib be developed
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Peggy Gandia, Laurence Malard, Cecile Arellano, Françoise Huguet, Thierry Lafont, Etienne ChatelutAbstract:Purpose The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for Imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both Imatinib and its main active metabolite (N-desmethylImatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of Imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations. Patients and methods The quantification of unbound fraction of Imatinib and N-desmethyl-Imatinib was performed using plasma ultrafiltration coupled with LC‐MS/ MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients. Results The mean unbound fractions of Imatinib and N-desmethyl-Imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for Imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for Imatinib and 34 % for N-desmethylImatinib. No correlation was observed between these measured individual Imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-Imatinib/Imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with interindividual variabilities of 71 and 86 %, respectively. Conclusion The large inter-individual variability for the unbound fraction of both Imatinib and N-desmethyl-Imatinib warrants further evaluation of the pharmacokinetic‐pharmacodynamic relationship as a potential relevant marker of Imatinib therapeutic outcomes.
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determination of unbound fraction of Imatinib and n desmethyl Imatinib validation of an uplc ms ms assay and ultrafiltration method
Analytical Abstracts, 2012Co-Authors: Cecile Arellano, Peggy Gandia, Rutchanna Jongejan, Thierry Lafont, Etienne ChatelutAbstract: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.
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Determination of unbound fraction of Imatinib and N-desmethyl Imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method
Journal of Chromatography B, 2012Co-Authors: Cecile Arellano, Peggy Gandia, Rutchanna Jongejan, Thierry Lafont, Etienne ChatelutAbstract:Abstract 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.
Jonathan C. Trent - One of the best experts on this subject based on the ideXlab platform.
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Imatinib mesylate in the treatment of gastrointestinal stromal tumour.
Expert Opinion on Pharmacotherapy, 2005Co-Authors: Dejka M. Steinert, John C. Mcauliffe, Jonathan C. TrentAbstract:Imatinib mesylate is a selective and potent small-molecule inhibitor of tyrosine kinases, including Kit, platelet-derived growth factor receptor, and the BCR–Abl fusion protein. Kit plays an important role in gastrointestinal stromal tumours (GISTs) and is one of the most exciting therapeutic targets discovered so far. Clinical trials have consistently shown the dramatic efficacy of Imatinib mesylate in patients with GIST. This article will review the development and pharmacology of this small-molecule inhibitor and summarise the clinical trials of Imatinib mesylate for the treatment of GIST. Although Imatinib mesylate has significantly improved the outcomes of most patients with advanced GIST, unanswered questions remain: what is the role of Imatinib mesylate in the pre- and postoperative settings? What is the mechanism of the antitumour activity of Imatinib? How do you manage patients whose tumours are refractory to Imatinib mesylate?
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a missense mutation in kit kinase domain 1 correlates with Imatinib resistance in gastrointestinal stromal tumors
Cancer Research, 2004Co-Authors: Lei L. Chen, Jonathan C. Trent, Gregory N Fuller, Latha Ramdas, Wei Zhang, A K Raymond, Victor G Prieto, Caroline O Oyedeji, Kelly K Hunt, Raphael E PollockAbstract:KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after Imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to Imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six Imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive Imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-Imatinib or post-Imatinib residual quiescent GISTs, and is strongly correlated with Imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT .
Cecile Arellano - One of the best experts on this subject based on the ideXlab platform.
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should therapeutic drug monitoring of the unbound fraction of Imatinib and its main active metabolite n desmethyl Imatinib be developed
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Peggy Gandia, Laurence Malard, Cecile Arellano, Françoise Huguet, Thierry Lafont, Etienne ChatelutAbstract:Purpose The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for Imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both Imatinib and its main active metabolite (N-desmethylImatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of Imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations. Patients and methods The quantification of unbound fraction of Imatinib and N-desmethyl-Imatinib was performed using plasma ultrafiltration coupled with LC‐MS/ MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients. Results The mean unbound fractions of Imatinib and N-desmethyl-Imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for Imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for Imatinib and 34 % for N-desmethylImatinib. No correlation was observed between these measured individual Imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-Imatinib/Imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with interindividual variabilities of 71 and 86 %, respectively. Conclusion The large inter-individual variability for the unbound fraction of both Imatinib and N-desmethyl-Imatinib warrants further evaluation of the pharmacokinetic‐pharmacodynamic relationship as a potential relevant marker of Imatinib therapeutic outcomes.
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determination of unbound fraction of Imatinib and n desmethyl Imatinib validation of an uplc ms ms assay and ultrafiltration method
Analytical Abstracts, 2012Co-Authors: Cecile Arellano, Peggy Gandia, Rutchanna Jongejan, Thierry Lafont, Etienne ChatelutAbstract: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.
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Determination of unbound fraction of Imatinib and N-desmethyl Imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method
Journal of Chromatography B, 2012Co-Authors: Cecile Arellano, Peggy Gandia, Rutchanna Jongejan, Thierry Lafont, Etienne ChatelutAbstract:Abstract 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.
