Article Figures & Data
Figures
- Fig. 1.
Uptake of sorafenib and sunitinib by solute carriers in vitro. Accumulation of sorafenib (A) and sunitinib (B) by X. laevis oocytes expressing OATP1A2, OATP1B1, OATP1B3, and OCT1 or HEK293 cells expressing OAT1, OAT3, OCTN1, and OCTN2. Oocytes or HEK293 cells were incubated with sorafenib (0.35-1.5 μmol/L) or sunitinib (0.15-0.45 μmol/L) for 1 h. Mean ± SD percent of water-injected control from 9 to 27 observations; a single control column is shown for all experiments combined. Prototypical substrates for each transporter were evaluated with each experiment as a positive control (black column).
- Fig. 2.
Transport of sorafenib and sunitinib by ABC transporters in vitro. A, transcellular transport of sorafenib and sunitinib in LLC-PK1 cells expressing ABCB1. Cells were incubated with 1 μmol/L drug for 1, 2, 3, and 4 h. Data represent six observations and are expressed as ABCB1-mediated Papp (B-to-A)/Papp (A-to-B) ratio. *, P < 0.05 versus ABCB1 (A and B). B, accumulation of sorafenib and sunitinib in Saos-2 cells overexpressing ABCG2 or ABCC4 or MDCKII cells overexpressing ABCC2. Cells were incubated with 1 μmol/L drug for 4 h. Mean ± SD percent control from 6 to 9 observations from 2 to 3 independent experiments; a single control column is shown for all experiments combined. Prototypical substrates for each transporter were evaluated with each experiment as a positive control (black column). *, P < 0.05 versus control.
- Fig. 3.
Inhibition of ABCB1 and ABCG2 function by sorafenib and sunitinib in vitro. Sorafenib (A) and sunitinib (B) decreased the efflux of Hoechst 33342 in Saos-2 cells expressing human ABCG2. Sorafenib (C) and sunitinib (D) decreased the efflux of calcein in LLC-PK1 cells expressing ABCB1. Cells were incubated with increasing drug concentrations for 1 h. Flow cytometry was used to assess Hoechst 33342 and calcein cellular efflux. Mean ± SD of 2 observations. Representative of 2 to 3 independent experiments. The lines represent the fit of a maximum effect model to the data.
- Fig. 4.
Inhibition of ABCC2 and ABCC4 function by sorafenib and sunitinib in vitro. Sorafenib and sunitinib inhibited the efflux of docetaxel in MDCKII cells overexpressing ABCC2 (A) and PMEA in Saos-2 cells overexpressing ABCC4 (B). Cells were incubated with 20 μmol/L sorafenib or sunitinib or 50 μmol/L MK571, an inhibitor of ABCC transporters, for 15 min followed by coincubation with 5 μmol/L docetaxel or 1 μmol/L PMEA for 4 h. Mean ± SD percent change of cellular accumulation of the prototypical substrates docetaxel or PMEA from 6 to 9 observations from 2 to 3 independent experiments.
- Fig. 5.
Effect of sorafenib on ATPase hydrolysis by ABCC2. Sorafenib inhibits vanadate-sensitive baseline and maximal ATPase activity of human ABCC2 expressed in membrane vesicles. Increasing concentrations of sorafenib were incubated with vesicles for 10 min. Representative of 2 to 3 experiments done in duplicate.
- Fig. 6.
Role of ABCB1 in the plasma pharmacokinetics and brain penetration of sorafenib and sunitinib in mice. Plasma concentration-time curves for sorafenib (A) and sunitinib (C) in wild-type and Abcb1 knockout mice. Brain penetration of sorafenib (B) and sunitinib (D) in wild-type and Abcb1 knockout mice. Sorafenib (40 mg/kg) or sunitinib (20 mg/kg) was administered orally to mice, plasma samples were obtained at 1, 2, and 4 h after treatment, and whole-brain tissue homogenate was collected at 4 h. Brain penetration was determined as the brain concentration at 4 h divided by the plasma AUC0-4 h. Mean ± SD from 2 to 3 independent experiments (6-9 observations per time point).
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Volume 15, Issue 19
