LAUSR

ABSTRACT This study was performed to determine the primary factor(s) governing the oral absorption of edaravone, a novel anti‐oxidant for the treatment of amyotrophic lateral sclerosis, in rats. While the aqueous solubility of edaravone widely varied depending on the vehicle used, the oral bioavailability of the drug was not low when it was adequately solubilized, as evidenced by the fact that the oral exposure was high (in terms of the absolute bioavailability of 50–90%) at all dose ranges (i.e., 0.5–27 mg/kg) under solubilized conditions in rats. The sum of the in vitro clearance values for edaravone, 12.7 mL/(min × kg), obtained from metabolic stability studies with tissue‐homogenates from the rat liver, kidney, intestine, and with the rat plasma, was found to be virtually identical to the systemic clearance of the drug in rats. It was noted that the liver represented over 83.9% of the total elimination with a hepatic extraction ratio of approximately 0.137, indicative of the minor role of hepatic first pass metabolism in the systemic absorption of edaravone after its oral administration. In studies with Ussing chamber with rat intestinal segments and Madin‐Darby canine kidney (MDCKII) cells, edaravone was found to be highly permeable (i.e., Papp over 10 × 10−6 cm/s), and appeared to be a substrate for rat P‐glycoprotein (P‐gp; estimated Km of 421 &mgr;M). In contrast, however, the drug did not appear to be a substrate for human P‐gp in transport studies with MDCKII‐hMDR1 cells. Collectively, these observations suggest that the primary determining factor for the intestinal absorption of edaravone is its solubilization in vehicle/intestinal fluids, rather than permeability, pre‐systemic first‐pass metabolism, or efflux transport. Considering the fact that the newly approved indication of the drug would require prolonged administration, probably via oral administration, the findings reported herein provide relevant information regarding its use. Graphical abstract Figure. No Caption available.