Received for publication September 4, 2007.
Revised January 23, 2008.
Accepted for publication January 24, 2008.

Identification of a Novel Glucosylsulfate Conjugate as a Metabolite of ARQ 501 (-lapachone) in Mammals

Abstract

ARQ 501 (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione) is a fully synthetic version of the natural product -lapachone which has been isolated from the lapacho tree (Tabebuia impetiginosa or Tabebuia avellanedae) and has demonstrated promising anti-cancer activity. ARQ 501 formulated with hydroxypropyl--cyclodextrin (HPCD) 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). While other glucosylsulfate conjugates have been identified as metabolites of pesticides in cotton plants and in crustaceans as phase II metabolites of pyrenes, none has been previously identified in mammals. Data reported here identify a novel metabolic pathway for humans.

Key words: glucuronidation, mass spectrometry, metabolite identification, phase II drug metabolism, sulfate conjugation, sulfotransferases, UDP glucuronyltransferases