title: Pre-systemic metabolism prevents in vivo antikinetoplastid activity of N1,N4-substituted 3,5-dinitro sulfanilamide, GB-II-150.
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.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. diwu88@hotmail.com
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Tesmol G
authors.initials: TG
authors.lastname: George
authors.forename: Eunju
authors.initials: E
authors.lastname: Hurh
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D016830:Kinetoplastida / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013424:Sulfanilamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; C513509:N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide; D013424:Sulfanilamides; D014404:Tubulin