Pre-systemic metabolism prevents in vivo antikinetoplastid activity ofN1,N4-substituted 3,5-dinitro sulfanilamide, GB-II-150

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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 N1- and N4-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.

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