Abstract 3534: Proposed pathway of disposition of ON 01910. Na, a novel clinical trial stage anti-cancer agent: Implicaton of Mrp2 in biliary excretion in the isolated perfused rat liver system

Abstract

Abstract Introduction: ON 01910. Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and Phase II trials. Preclinical studies indicate that the compound preferentially distributes to the liver but is not extensively metabolized in vivo The purpose of this study was to evaluate the disposition of ON 01910. Na employing the isolated perfused rat liver (IPRL) model. The specific goals were to 1) Assess the dose-linearity of ON 01910. Na disposition; 2) Probe the role of the Mrp2 transporter on ON 01910. Na biliary excretion; and 3) Establish the effect of concurrent dosing with oxaliplatin and doxorubicin on ON 01910. Na hepatobiliary disposition. Methods: Perfusion experiments (n=3/group) were performed at 4 doses (0.8, 4, 8, 20 mg), targeting a range of perfusate levels between 10 and 250 ug/ml. ON 01910. Na (10 ug/ml) disposition was then studied in the presence of doxorubicin (2.5 ug/ml) and oxaliplatin (2 ug/ml). IPRL experiments were also conducted using livers from Mrp2 deficient rats. ON 01910. Na was assayed in perfusate and bile samples by HPLC. Results: ON 01910. Na parameter estimates are provided in the table below. The compound displayed nonlinear excretion in the IPRL, and ON 01910. Na disposition was altered in mrp2-deficient rats. The effect of co-administered chemotherapeutic agents is being investigated. Conclusions: ON 01910. Na showed extensive biliary excretion in the IPRL, and IPRL findings correlated with in vivo data in rats. ON 01910. Na biliary transport appears to be mediated in part by Mrp2.ON 01910. Na Disposition in the IPRLaPARAMETERON 01910. Na (µg/ml) 10.050.0100250t1/2 (hr)0.460 (0.0340)0.327 (0.0674)0.585 (0.0810)1.26 (0.318)Cmax (µg/ml)11.3 (1.75)56.1 (7.12)106 (11.2)257 (658)AUC (0-∞) (µg*min/ml)290 (87.1)1480 (73.0)4010 (963)21100 (2580)Cl (ml/min)2.91 (0.753)2.71 (0.134)2.08 (0.557)0.959 (0.125)% Drug Excreted in Bile57.2 (5.04)59.2 (7.40)68.4 (0.870)45.6 (2.66)aData presented as mean (standard deviation) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3534.