Legends for Figures
Fig. 1 Structure of ningetinib (A) and M1 (B)
Fig. 2 Mean plasma concentration-time profiles of ningetinib and M1 in patients with NSCLC following oral administration of 60 mg of ningetinib without (A1/A2) and with (B1/B2) 250 mg of gefitinib.
Fig. 3 Metabolic stability of ningetinib and formation of M1 in human primary hepatocytes (A), human liver microsomes (B), human intestinal microsomes (C), human lung microsomes (D) and human kidney microsomes (E) versus incubation time. Each point represents the mean of three independent experiments ± SD (n = 3).
Fig. 4 Inhibitory effect of gefitinib on M1 formation mediated by human recombinant HLMs (A1/A2/A3), CYP1A1 (B1/B2/B3), CYP1B1 (C1/C2/C3) or CYP2C9 (D1/D2/D3). The figures above represent the Dixon (1953) method. The figures in the middle represent the Cornish-Bowden (1974) method. The figures below represent the mixed-type inhibition. Each point represents the mean of three independent experiments ± SEM (n = 3). “I” means gefitinib and “S” means ningetinib.
Fig. 5 Tissue distribution of ningetinib and M1 in ICR mice after an oral dose of ningetinib (10 mg·kg-1). (A) ningetinib, (B) M1, (C) M1 to ningetinib ratio. Each point represents the mean of three independent experiments ± SD (n = 3).
Fig. 6 Inhibitory effect of ningetinib and gefitinib on M1 efflux in MDCKII-MDR1 (A1/A2), MDCK II-BCRP (B1/B2) and MDCK II-MRP2 (C1/C2) cells. Each point represents the mean of three independent experiments. Remaining activity means percentage of ER values of M1 in the inhibitor group versus the control group.
Fig. 7 Mean blood concentration-time profiles of D6-M1 in mice following intravenous injection of 0.5 mg/kg D6-M1 with or without 40 mg·kg-1 ningetinib. Each point represents the mean of three independent experiments ± SD (n = 7). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. the control