In Vitro Screening of Six Protein Kinase Inhibitors for Time-Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug-Drug Interactions.

摘要: Several protein kinase inhibitors have been reported to affect cytochrome P450 (CYP) 3A by time-dependent inhibition. Herein, we tested a set of six for inhibition CYP2C8 and CYP3A4 in human liver microsomes. Dovitinib, midostaurin nintedanib exhibited an increased after 30-min. pre-incubation with NADPH, as compared no (IC50 shift >1.5). Masitinib, trametinib vatalanib did not or <1.5). The inhibitory mechanism nintedanib, but dovitinib, was consistent irreversible mechanism-based maximal inactivation rate (kinact ) inhibitor concentration that supports half-maximal (KI values were 0.052 1/min. 2.72 μM, 0.025 17.3 respectively. According static predictions, unlikely cause drug-drug interactions clinically used doses whereas predicted increase the plasma exposure CYP3A4-dependent substrates several fold. Furthermore, based on reversible inhibition, masitinib sensitive ≥2-fold. In summary, our data identify detect risk between substrates, masitinib, substrates. liability CYP enzymes may long-term consequences, terms toxicities.