Abstract 2462: Pharmacokinetics and <i>in vivo</i> metabolism of the naphthofuran NSC373981 in male nu/nu mice.
Authors: Joel M. Reid, Sarah A. Buhrow, Renee M. McGovern, Joseph M. Covey, Matthew M. Ames
Journal: Cancer Research (2013)

Abstract NSC 373981 is 1-ethanol, 2-nitro-naphtho[2,1-b]furan that has demonstrated activity in the NCI60 anticancer screen and in the mouse hollow-fiber assay. Growth inhibitory activity was also observed in several xenograft models. There is some evidence that antitumor activity is greater in vivo than would be predicted by the in vitro results, suggesting the possibility of activating metabolism. While the mechanism of anticancer activity is unknown, naphthofurans have been reported to modulate certain nuclear receptors. The purpose of this study was to characterize the plasma pharmacokinetics of NSC 373981 following i.v. and i.p. administration to athymic nude mice and to characterize potential metabolites of this compound in plasma, urine, and bile. We developed and validated suitable positive ionization LC/MS/MS methodology for measuring NSC 373981 that utilized liquid extraction with 1-chlorobutane and MS/MS detection with the 258&amp;gt;212 and 244&amp;gt;169 transitions, respectively, for NSC 373981 and NSC 329226, an analog that was used as the internal standard. Baseline separations were achieved on a Polaris C18 column under a mobile phase consisting of 70:30 methanol:water containing 0.1% formic acid. Standard curves were linear over the concentration range 2.5-1000 ng/mL with a lower limit of detection of 2.5 ng/mL. NSC 373981 was stable under acidic, neutral and basic conditions, as well as human and mouse plasma during 24-hr incubation at 37°C. NSC 373981 pharmacokinetics were characterized in male nu/nu mice after a 37.5 mg/kg i.v. dose or a 150 mg/kg i.p. dose. Plasma, bile, urine and feces were collected for 24-hr after drug administration. Following i.v. administration, the peak concentration was &amp;gt; 5.9 μg/mL and the terminal elimination half-life was 1.2 hours. Volume of distribution and plasma clearance values were 694 ml and 390 mL/hr, respectively. Following i.p. administration, NSC373981 reached a peak concentration of 2.1 μg/mL at 15 minutes and the terminal elimination half-life was 36.8 hours. The i.p. bioavailability of NSC373981 was 58%. In vivo metabolite profiles were characterized in plasma, urine, feces, and bile. We detected several Phase I metabolites in these samples including those produced by reduction of the aromatic nitro group, oxidation of the primary alcohol moiety on the reduced metabolite, oxidation of the primary alcohol moiety, benzylic hydroxylation, hydroxylation and dihydrodiol formation on the naphthalene moiety, and Phase II metabolites including glucuronidation of the carboxylic acids and a glutathione metabolite of hydroxylated NSC 373981. Supported by NCI contract N01-CM-2011-00014. Citation Format: Joel M. Reid, Sarah A. Buhrow, Renee M. McGovern, Joseph M. Covey, Matthew M. Ames. Pharmacokinetics and in vivo metabolism of the naphthofuran NSC373981 in male nu/nu mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2462. doi:10.1158/1538-7445.AM2013-2462