Thermosensitive molecularly imprinted poly(1-vinyl-2-pyrrolidone/methyl methacrylate/N-vinylcaprolactam) for selective extraction of imatinib mesylate in human biological fluid.

The efficiency of a molecularly imprinted polymer as a selective packing material for the solid-phase extraction of imatinib mesylate sorption was investigated. The molecularly imprinted polymer was prepared using N,N'-methylenebisacrylamide as a cross-linker agent, N-vinylcaprolactam as a thermo-sensitive monomer, 1-vinyl-2-pyrrolidone and methyl methacrylate as functional monomers, azobisisobutyronitrile as an initiator and imatinib mesylate as a template. The drug-imprinted polymer was identified by Fourier transform infrared spectroscopy, thermogravimetric analysis, elemental analysis, and scanning electron microscopy. It was found that this polymer can be used for determination of trace levels of imatinib mesylate with a recovery percentage that could reach over 90%. Furthermore, the synthesized molecularly imprinted polymer indicated higher selectivity towards imatinib mesylate than other compounds. From isotherm study, the equilibrium adsorption data of imatinib mesylate by imprinted polymer were analyzed by Langmuir, Freundlich, and Temkin isotherm models. The developed method was used for determination of imatinib mesylate in human fluid samples by high performance liquid chromatography with excellent results.

Chitosan grafted onto Fe3O4@poly(N-vinylcaprolactam) as a new sorbent for detecting Imatinib mesylate in biosamples using UPLC-MS/MS.

Fe3O4 nanoparticles with chitosan grafted onto poly(N-vinylcaprolactam) copolymers are synthesized and showed dual sensitivity to temperature and pH. The nanoparticles were characterized by different techniques and two aspects of their applications were evaluated using Imatinib mesylate drug as a model. The first studied application of these nanoparticles was the extraction and pre-concentration of Imatinib mesylate from biological samples. Parameters such as sorbent dosage and extraction and desorption time can affect Imatinib mesylate extraction and were studied by Box-Behnken design and response surface methodology, while the one-factor-at-a-time approach was used to assessed the sample pH and elution solvent type and amount. The determination and quantification were accomplished by ultra-performance liquid chromatography-mass spectrometry. The limit of quantification of the approach was 1.0 ng mL-1. Inter/intraday precision was obtained as 3.4-6.7% and 5.1-7.7%, respectively. Also, the modified nanoparticles were studied in basic in vitro drug delivery research which led to satisfactory results.

New spectrophotometric/chemometric assisted methods for the simultaneous determination of imatinib, gemifloxacin, nalbuphine and naproxen in pharmaceutical formulations and human urine.

In this paper, novel univariate and multivariate regression methods along with model-updating technique were developed and validated for the simultaneous determination of quaternary mixture of imatinib (IMB), gemifloxacin (GMI), nalbuphine (NLP) and naproxen (NAP). The univariate method is extended derivative ratio (EDR) which depends on measuring every drug in the quaternary mixture by using a ternary mixture of the other three drugs as divisor. Peak amplitudes were measured at 294nm, 250nm, 283nm and 239nm within linear concentration ranges of 4.0-17.0, 3.0-15.0, 4.0-80.0 and 1.0-6.0µgmL-1 for IMB, GMI, NLP and NAB, respectively. Multivariate methods adopted are partial least squares (PLS) in original and derivative mode. These models were constructed for simultaneous determination of the studied drugs in the ranges of 4.0-8.0, 3.0-11.0, 10.0-18.0 and 1.0-3.0µgmL-1 for IMB, GMI, NLP and NAB, respectively, by using eighteen mixtures as a calibration set and seven mixtures as a validation set. The root mean square error of predication (RMSEP) were 0.09 and 0.06 for IMB, 0.14 and 0.13 for GMI, 0.07 and 0.02 for NLP and 0.64 and 0.27 for NAP by PLS in original and derivative mode, respectively. Both models were successfully applied for analysis of IMB, GMI, NLP and NAP in their dosage forms. Updated PLS in derivative mode and EDR were applied for determination of the studied drugs in spiked human urine. The obtained results were statistically compared with those obtained by the reported methods giving a conclusion that there is no significant difference regarding accuracy and precision.

Novel sulphur-containing imatinib metabolites found by untargeted LC-HRMS analysis.

Untargeted metabolite profiling using high-resolution mass spectrometry coupled with liquid chromatography (LC-HRMS), followed by data analysis with the Compound Discoverer 2.0™ software, was used to study the metabolism of imatinib in humans with chronic myeloid leukemia. Plasma samples from control (drug-free) and patient (treated with imatinib) groups were analyzed in full-scan mode and the unknown ions occurring only in the patient group were then, as potential imatinib metabolites, subjected to multi-stage fragmentation in order to elucidate their structure. The application of an untargeted approach, as described in this study, enabled the detection of 24 novel structurally unexpected metabolites. Several sulphur-containing compounds, probably originating after the reaction of reactive intermediates of imatinib with endogenous glutathione, were found and annotated as cysteine and cystine adducts. In the proposed mechanism, the cysteine adducts were formed after the rearrangement of piperazine moiety to imidazoline. On the contrary, in vivo S-N exchange occurred in the case of the cystine adducts. In addition, N-O exchange was observed in the collision cell in the course of the fragmentation of the cystine adducts. The presence of sulphur in the cysteine and cystine conjugates was proved by means of ultra-high resolution measurements using Orbitrap Elite. The detection of metabolites derived from glutathione might improve knowledge about the disposition of imatinib towards bioactivation and help to improve understanding of the mechanism of its hepatotoxicity or nephrotoxicity in humans.