Abstract 3605: Enterohepatic circulation of indolecarboxamide ML-970 (NSC 716970), an investigative anticancer agent

Abstract

Abstract ML-970 (NSC 716970), an analog of CC-1065 (a DNA minor-groove binding agent) is under preclinical investigation as a novel anticancer agent. The compound has shown in vitro and in vivo anti-cancer activity. As part of the preclinical evaluation of this agent, we carried out pharmacokinetic studies of ML-970 in CD-1 and nude mice. Of interest, we observed that there was minimal urinary and fecal excretion of the agent within the first 24 hr and relatively low concentrations of the compound in tissues examined (lungs, kidneys, heart, spleen, brain). Additionally, the compound was still detectable at low levels in the plasma for at least 8 hr, and in tissues for at least 24 hr after administration, regardless of the routes of administration. Although high levels of plasma protein binding of the compound may be partially responsible, it was apparent that other factors might be contributing. To examine the underlying mechanism, we performed a pharmacokinetic study evaluating the distribution of the compound in tissues, organs, and organ contents (plasma, liver, lungs, kidneys, spleen, heart, brain, stomach, stomach contents, small intestine, small intestine contents, large intestine, large intestine contents, gallbladder, muscle, urine and feces) after i.v. and oral administration. We found the highest levels of the compound in the gallbladder, small intestine, small intestine contents, large intestine contents and liver, regardless of route of administration. Concentrations of 314.7μg/g, 1383.5μg/g, and 392.6μg/g for 0.5, 2, and 8 hr after i.v. injection, and 28.0μg/g, 313.1μg/g, and 123.7μg/g for 0.5, 2, and 8 hr after oral administration, respectively, were observed for the gallbladder. Average concentrations higher than 19 μg/g were found in the other tissues for at least one time point (range: 19.3μg/g to 286.2μg/g). The high concentrations present in gastrointestinal and hepato-biliary organs, persistence of the compound, and relatively low levels of urinary and fecal excretion during the first 24 hr, indicate that the compound undergoes enterohepatic circulation. These results should be useful for interpretation of future preclinical and clinical developmental studies of ML-970. (This work was supported by NCI Contract N01-CM-52207.) 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 3605.