PMC

Concentration dependance of raltitrexed uptake is shown as Eadie-Hofstee plots. The solid line represents the fitted line obtained by nonlinear regression analysis. Each data point with an error bar represents the mean value and S.E. (n = 3).

The uptake of [³H]ochratoxin A (0.1 μM), [³H]pitavastatin (0.1 μM), raltitrexed (30 μM), [³H]pravastatin (0.1 μM), [³H]cyclic guanosine monophosphate (cGMP, 0.1 μM), [³H]2,4D (0.1 μM), and [¹⁴C]urate (0.1 μM) by the membrane vesicles that were prepared from HEK293 cells expressing MRP4 and green fluorescent protein was determined at 37°C for 5 min in medium that contained 5 mM ATP (■) or AMP (□). Each bar with an error bar represents the mean value and standard error (S.E.) (n = 3).

■, data for mOatp1a4 and mOat3-expressing cells; □, data for mock cells. Each bar with an error bar represents the mean value and S.E. (n = 3). Daggers represent statistically significant differences between mock and Oatp1a4 (or Oat3)-expressing cells in control conditions; †, P < 0.05; ††,P < 0.005; †††, P < 0.0005. Asterisks represent statistically significant differences between in the absence and presence of inhibitors in transporter expressing cells; *, P < 0.05; **, P < 0.005; ***, P < 0.0005.

Mice received a continuous intravenous infusion for 120 min of either quinidine or dantrolene at a dose of 8 or 2 μmol/h/kg after priming doses of 6 or 4 μmol/kg, respectively. The plasma, brain, and CSF concentrations of quinidine and dantrolene were determined at the end of infusion. ■, data for WT mice; □, data for Mrp4^-/- mice. Each data point and bar with an error bar represents the mean value and S.E. obtained from three to four mice.

Mice received a continuous subcutaneous infusion of either methotrexate or raltitrexed at a dose of 80 or 160 μg/h/mouse, respectively, for 19 h with an osmotic pump. The plasma, brain and CSF concentrations of methotrexate and raltitrexed were determined at the end of the infusion. □, data for WT mice; ■, data for Mrp4^-/- mice. Each bar with an error bar represents the mean value and S.E. obtained from four mice. Asterisks represent statistically significant differences between WT and Mrp4^-/- mice: **, P < 0.01.

At 15 min after the injection of GF120918 (17 μmol/kg, closed symbols) or solvent alone (open symbols), the mice received a constant intravenous infusion of methotrexate and raltitrexed at doses of 8 and 12 μmol/h/kg. The plasma concentrations of methotrexate and raltitrexed were determined at the designated times in WT (circles) and Mrp4^-/- mice (squares). The tissue-to-plasma ratio was calculated at 90 min. Each data point and bar with an error bar represent the mean value and standard error (S.E.) obtained from three to four mice. Asterisks represent statistically significant differences between WT and Mrp4^-/- mice; *, P < 0.05; **, P < 0.005. Daggers represent statistically significant differences between control and GF120918-pretreated mice; †, P < 0.05; ††, P < 0.005; †††, P < 0.0005.