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