alexa Pre-systemic metabolism prevents in vivo antikinetoplastid activity of N1,N4-substituted 3,5-dinitro sulfanilamide, GB-II-150.
Chemical Engineering

Chemical Engineering

Journal of Analytical & Bioanalytical Techniques

Author(s): Wu D, George TG, Hurh E, Werbovetz KA, Dalton JT

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Abstract We previously showed that N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (denoted GB-II-150) possesses selective antimicrotubule activity against Leishmania donovani and Trypanosoma brucei in vitro [Bhattacharya, G., Herman, J., Delfin, D., Salem, M.M., Barszcz, T., Mollet, M., Riccio, G., Brun, R., Werbovetz, K.A., 2004. Synthesis and antitubulin activity of N(1)- and N(4)-substituted 3,5-dinitro sulfanilamides against African trypanosomes and Leishmania. Journal of Medicinal Chemistry 47, 1823-1832]. When GB-II-150 was administered orally to male Sprague-Dawley rats, extensive first-pass metabolism of the compound was observed and the oral bioavailability was zero. GB-II-150 displayed a half-life of 170 min and a clearance of 31.5 mL/min/kg in rats when administered intravenously. In vitro metabolism studies indicated that less than 5\% of GB-II-150 remained intact after a 60-min incubation with rat liver S9 fraction. As expected, the compound was extensively metabolized, with the major products resulting from N1-ring oxidation, N4-alkane oxidation, N4-oxidation, and nitro reduction. These data indicate that GB-II-150 undergoes rapid and extensive first-pass metabolism, precluding the attainment of effective systemic drug concentrations and explaining the lack of in vivo antitrypanosomal activity of this compound. This article was published in Life Sci and referenced in Journal of Analytical & Bioanalytical Techniques

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