Huskey, Su-Er, Zhu, Chunqi, Forseth, Ry, Gu, Helen, Simon, Oliver, Eggimann, Fabian, Kittelmann, Matthias, Luneau, Alexandre, Vargas, Alexandra, Li, Hongmei, Wang, Lai, Einolf, Heidi, Zhang, Jin, Favara, Sarah, He, Handan and Mangold, James (2016) Identification of three novel ring expansion metabolites of KAE609 in rat, dog, and human, a new spiroindolone agent for the treatment of malaria. Drug metabolism and disposition, Identification of three novel ring expansion metabolites of KAE609 in rat, dog, and human, a new spiroindolone agent for the treatment of malaria, 44 (5). pp. 653-664. ISSN 1521-009X (Online)

Abstract

KAE609 is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. Following oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤ 11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥ 93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Amongst the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1, 2-acyl shift to form a ring expansion metabolite M37. The in vitro metabolism of KAE609 in hepatocytes was investigated to understand this novel biotransformation. The metabolism of KAE609 was qualitatively similar across the species studied, thus further investigation was conducted using human recombinant CYP enzymes. The ring expansion reaction was found to be primarily catalyzed by CYP3A4 yielding M37. M37 was then subsequently oxidized to M18 by CYP3A4, and hydroxylated to M23 primarily by CYP1A2. Interestingly, M37 was colorless while M18 and M23 showed orange yellow color. The source of the color of M18 and M23 was attributed to their extended conjugated system of double bonds in the structures.

Item Type:	Article
Keywords:	metabolism, identification, malaria, KAE609, ring expansion, spiroindolone, CYP enzymes, structural elucidation
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27475