Résumé
Abemaciclib (ABE) has been reported to cause gastrointestinal toxicity. Therefore, it is important to investigate the question of whether abemaciclib administration causes nephrotoxicity in the gastrointestinal tract, and if so, what pathophysiological pathways it follows. In this study, the relationship between ABE administration and nephrotoxicity and the protective effect of Curcumin (CMN) was investigated. Forty female rats were equally divided into the sham, dimethyl sulfoxide (DMSO), CMN, abemaciclib and ABE+CMN groups. Aquaporin (AQP) 1-7, TNF-?, IL-1?, intercellular adhesion molecule (ICAM)-1, IL-10 and IL-37 levels in serum and kidney tissue homogenates were measured by ELISA. In addition, Urea and Creatinine were measured in serum samples. Furthermore, histopathological examination was performed in kidney tissues and Bax, Caspase-3 and Bcl-2 expression levels were determined immunohistochemically. The levels of AQP1-7 and IL-10 in the ABE group were partially lower than in the other groups, while the ratio of TNF?, IL-1?, MDA, caspase-3 and Bax/Bcl2 were high. In addition, kidney tissue was examined histopathologically. However, AQP1 and 7 levels in the ABE+CMN group were higher than in the ABE group, while TNF-?, IL-1?, MDA, Caspase-3 levels and Bax/Bcl2 ratio were low. In addition, the poor histopathological changes in the ABE group were largely restored in the ABE+CMN. The data presented that ABE in rats can adversely affect functions and histology of kidneys through the increase in oxidative stress, pro-inflammatory cytokines and apoptosis, but CMN therapy may be protective against the nephrotoxic effects of ABE
Résumé
A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid samples.The method was validated over a concentration range of 0.2-500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex? Fs column.Detection was performed on a Sciex QTRAP 6500+mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization.The intra-and inter-batch accuracy as well as the precision of the method for all matrices was within±20％and≤20％at the lower limit of quantification,and within±15％and≤15％for other quality control levels for all analytes.The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis.The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.