Binimetinib Is a Potent Reversible and Time-Dependent Inhibitor of Cytochrome P450 1A2

Abstract

Binimetinib is a selective MEK1/2 inhibitor, which is indicative of melanoma. We aimed to investigate the inhibitory effect of binimetinib on cytochrome P450 using human liver microsomes. Binimetinib was demonstrated to display reversible and time-dependent inhibitory effects on human CYP1A2. Binimetinib can inhibit the activity of phenacetin deethylation with IC 50 of 5.6 μM. A 30 min preincubation of binimetinib with NADPH-supplemented human liver microsomes raised a significant left IC 50 shift (6.5-fold), from 5.69−0.88 μM. The inactivation parameters K inact and K I were 0.063 min −1 and 15.47 μM, and the half-life of inactivation was 11 min. Glutathione (GSH) and catalase/superoxide exhibited minor or no protective effect on binimetinib-induced enzyme inactivation. Trapping experiment by GSH induced a detection of GSH adduct, of which the formation was believed to be through the oxidation of electron-rich 1,4benzenediamine to reactive 1,4-diiminoquinone species. Cytochrome P450 3A4, 2C9, and 2D6 were involved in the bioactivation of binimetinib. In conclusion, binimetinib was proven to display reversible and time-dependent inhibitory effect on CYP1A2, which may have implications for the toxicity of binimetinib.

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

“…Binimetinib undergoes CYP3A4- and CYP2C9-mediated oxidations to the 1,4-diiminoquinone derivative 30 ) , which is chemically reactive and forms a glutathione adduct. Placements for the 1,4-diiminoquinone formation on CYP3A4 Template and on CYP2C9-Template were available at Rings B(A)-D(C)-K(J-I-G)-Q’(Q)-W ( Fig.…”

“…2F ), respectively. The 1,4-diiminoquinone formation, assessed as the glutathione adduct, is only in trace in recombinant CYP1A2 system 30 ) . The 1,4-diiminoquinone, however, inactivates CYP1A2.…”

“…The inhibitory actions of DSP-1053 was undetectable in individual recombinant CYP1A2 systems 29 ) . Bioactivation of binimetinib, assessed with formation of the GSH adduct, was detected in the presence of CYP2C9 and CYP3A4, but only in trace in the presence of CYP1A2 30 ) . Clear inhibitory phenomena of both metabolites to CYP1A2 were explained as the interference of Trigger-residue function on Template (3.2 Inactivation of CYP1A2 after other P450-mediated slight structural alterations).…”

Genotoxic C8-Arylamino-2′-deoxyadenosines Act as Latent Alkylating Agents to Induce DNA Interstrand Cross-Links

“…NaOCl, a potent oxidizing and halogenating agent, does not appear to significantly induce diiminoadenine presumably due to its lack of specificity toward ArNHdA oxidation. Interestingly, the proposed formation mechanism for ArNHdA-dG ICL is reminiscent of that for the glutathione (GSH) adducts of diamine-containing compounds such as the nonsteroidal anti-inflammatory drug nimesulide (Scheme C). , The metabolic oxidation of nimesulide generates a diiminoquinone electrophile, which is quenched by GSH to produce the nimesulide-GSH conjugate. On the basis of the results presented in this report and other studies in the literature, it appears that this NBS-mediated mechanism is not as robust with respect to purine oxidation and cross-link formation when compared to that of the one-electron oxidizing agents studied in these reports. ,, …”

Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug–Drug Interaction with Tacrine

“…Mechanism-based inactivators of CYP1A2 inhibit long-lasting and specific enzymatic activity, with significant effects at low concentrations. When inhibitors are combined with drugs metabolized by CYP1A2, inhibition of CYP1A2 activity delays drug elimination from the body, which may cause clinically meaningful drug interactions . Various dietary factors may modulate CYP1A2 activity due to the intake of a certain amount of furanocoumarins .…”