Identification of a novel glucosylsulfate conjugate as a metabolite of 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, beta-lapachone) in mammals.

Abstract

3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501) is a fully synthetic version of the natural product beta-lapachone, which has been isolated from the lapacho tree (Tabebuia impetiginosa or Tabebuia avellanedae) and has demonstrated promising anticancer activity. ARQ 501 formulated with hydroxypropyl-beta-cyclodextrin has successfully completed phase I clinical trials and is currently in several phase II human clinical trials for the treatment of pancreatic cancer, head and neck cancer, and leiomyosarcoma. The metabolites of ARQ 501 were investigated by low-resolution and high-resolution mass spectrometry in plasma from (nu/nu) mice, rats, and humans treated with the compound. The data for one of the metabolites identified are consistent with conjugation of ARQ 501 with a glucosylsulfate moiety (m/z 241; fragment ion). Although other glucosylsulfate conjugates have been identified as metabolites of pesticides in cotton plants and in crustaceans as phase II metabolites of pyrenes, none have been previously identified in mammals. Data reported here identify a novel metabolic pathway for humans.

• Authors: Ronald E Savage, Andrew N Tyler, Xiu-Sheng Miao, Thomas C K Chan
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 36 Issue 4 Pg. 753-8 (Apr 2008) ISSN: 1521-009X [Electronic] United States
• PMID: 18227145 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Naphthoquinones
• Sulfates
• beta-lapachone
• Glucose

Topics

• Animals
• Glucose (analysis, chemistry, metabolism)
• Humans
• Metabolic Networks and Pathways (physiology)
• Mice
• Mice, Nude
• Naphthoquinones (analysis, chemistry, metabolism)
• Sulfates (analysis, chemistry, metabolism)