Disposition of ON 01210.Na (Ex-RAD(R)), a novel radioprotectant, in the isolated perfused rat liver: probing metabolic inhibition to increase systemic exposure

• Published in: Journal of pharmaceutical sciences Vol. 102; no. 2; p. 732
• Main Authors: Tamhane, Mitalee, Maniar, Manoj, Ren, Chen, Benzeroual, Kenza E, Taft, David R
• Format: Journal Article
• Language: English
• Published: United States 01-02-2013
• Subjects: Animals; Liver - drug effects; Liver - metabolism; Male; Perfusion - methods; Protein Binding - physiology; Radiation-Protective Agents - metabolism; Radiation-Protective Agents - pharmacology; Rats; Rats, Sprague-Dawley; Sulfonamides - metabolism; Sulfonamides - pharmacology
• ISSN: 1520-6017
• DOI: 10.1002/jps.23391

ON 01210.Na (Ex-RAD) is a novel benzyl styryl sulfone analog, developed as a radioprotectant by Onconova Therapeutics Inc. The objectives of this research were to evaluate the hepatobiliary disposition of ON 01210.Na in the isolated perfused rat liver (IPRL) and to determine the effect of coadministration of ethacrynic acid (EA) on the pharmacokinetic profile of ON 01210.Na. EA acid was used as a prototypical inhibitor of glutathione-S-transferase inhibitor. ON 01210.Na was highly bound in IPRL perfusate proteins, and binding was significantly lower in the presence of EA. Dose-escalation studies (bolus dose, target concentrations 10-250 μg/mL) showed that ON 01210.Na followed nonlinear pharmacokinetics with hepatic clearance decreasing from 3.14 to 1.99 mL/min with increasing dose. ON 01210.Na underwent extensive metabolic degradation to its glutathione (GSH) adduct in liver. The GSH metabolite was mainly excreted into the bile. Coadministration of EA (1 mM) significantly inhibited the conversion of ON 01210.Na to its GSH conjugate, resulting in decreased clearance (approx. fivefold lower), and prolonged elimination from the perfusate. These preclinical studies suggest that EA is a potential pharmacoenhancer that can reduce the metabolism of ON 01210.Na in vivo, thereby increasing drug exposure and boosting radioprotective activity.