AG-348 activates WT PK-R in RBCs from healthy donors and in mice. (A) WT PK-R activity from RBCs from healthy donors incubated overnight with indicated concentrations of AG-348 (PEP = 0.1 mM). Mean, standard deviation, range, and number of experimental replicates are indicated in the column on right-hand side of panel. (B) ATP levels of healthy- donor RBCs incubated overnight with indicated concentrations of AG-348. (C) Concentration of AG-348 measured in plasma of mice dosed with AG-348 twice daily for 7 days at indicated dose levels. The bar graph depicts the calculated AUC_{0-12 hours} at each dose level. (D) PK-R activity in RBCs from mice dosed with AG-348 as described in panel C (PEP = 0.1 mM). For clarity, only the 150 mg/kg dose level is shown here. See supplemental Figure 2 for full data plots. The bar graph depicts the calculated AUC_{0-12 hours} at each dose level. (E) ATP levels and calculated AUC_{0-12 hours} in whole blood from mice dosed with AG-348 as described in panel D. (F) 2,3-DPG levels and calculated AUC_{0-12 hours} in whole blood from mice dosed with AG-348 as described in panel D. For clarity, only the 150 mg/kg dose level is shown in panels E and F. All error bars are standard deviations.