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. Author manuscript; available in PMC: 2018 Aug 24.
Published in final edited form as: Chem Res Toxicol. 2018 Jun 18;31(7):570–584. doi: 10.1021/acs.chemrestox.8b00005

Figure 4.

Figure 4

Effect of P450 inhibitors on sunitinib metabolite formation: (A) M1, (B) M3, and (C) M5. Sunitinib (10 μM) was incubated with pooled human liver microsomes (0.1 mg/mL) supplemented with 5 mM GSH in the presence or absence of P450-selective chemical inhibitors. The following chemical inhibitors were used to block the respective P450: α-naphthoflavone (1 μM, P540 1A2); furafylline (25 μM, P450 1A2); PPP, phenyl-piperidinyl propane (15 μM, P450 2B6); ticlopidine (5 μM, P450 2B6/2C19); sulfaphenazole (5 μM, P450 2C9); (+)-N-3-benzylnirvanol (5 μM, P450 2C19); quinidine (2 μM, P450 2D6); 4-methylpyrazole (100 μM, P450 2E1); ketoconazole (1 μM, P450 3A); and CYP3cide (2 μM, P450 3A4). Control incubations were carried out with the appropriate vehicle solvent control in the absence of inhibitor. Relative levels of metabolite formed were measured by LC–MS/MS. Metabolite levels (expressed as peak area ratio) under control conditions were: (A) 6.6 ± 1.4 for M1, (B) 0.04 ± 0.02 for M3, and (C) 0.01 ± 0.008 for M5. Percent (%) metabolite formation was based on comparison to vehicle control. The results are shown as the means ± SD from three independent experiments (n = 3) performed in triplicate each. Comparisons of inhibitor vs vehicle control were performed by unpaired two-tailed t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.