Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.
These results suggest that Bcrp1 plays an important role in the intestinal efflux of ME3277 and, probably, PM-10 and PM-11, metabolites of ME3229, and limits its BA after oral administration of ME3229.
An advantage of using LC-MS(/MS) for in vitro CYP inhibition screening is that it does not require extensive sample preparation and chromatographic separation. Attention must be paid, however, to ion suppression effects on analytes caused by the test compound as well as endogenous compounds. In this study, we have shown the ion suppression of 1'-hydroxymidazolam (analyte) and dextrorphan (IS) by erythromycin, as an example, which may cause over- or underestimation of CYP3A4 inhibition. To avoid this kind of effect, we proposed to use a stable isotope-labeled substrate and determine labeled metabolites by using unlabeled authentic compounds of each metabolite. We showed that CYP3A4 activity was determined with high accuracy and precision by using stable isotope-labeled midazolam even in the presence of an ion suppressor at high concentrations in the samples. This method is useful not only for the CYP inhibition screening but also for testing drug candidates to predict changes in metabolite formation by the possible co-administered drugs.
In the carnitine deficiency state induced by PVA, increased CLuptake owing to up-regulation of carnitine transporters is suggested to help maintain carnitine levels in some tissues.
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