title: The metabolism and pharmacokinetics of phospho-sulindac (OXT-328) and the effect of difluoromethylornithine.
abstract: OBJECTIVE
  Phospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics.
  
  
  METHODS
  PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice.
  
  
  RESULTS
  PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest C(max) and SSone the highest t(1/2) ; their AUC(0-24h) are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues.
  
  
  CONCLUSIONS
  Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xie
authors.forename: T
authors.initials: T
authors.lastname: Nie
authors.forename: G G
authors.initials: GG
authors.lastname: Mackenzie
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: N
authors.initials: N
authors.lastname: Ouyang
authors.forename: N
authors.initials: N
authors.lastname: Alston
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.forename: O T
authors.initials: OT
authors.lastname: Murray
authors.forename: P P
authors.initials: PP
authors.lastname: Constantinides
authors.forename: L
authors.initials: L
authors.lastname: Kopelovich
authors.forename: B
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000517:prevention & control; D003600:Cytosol / Q000378:metabolism; D000518:Eflornithine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C553002:OXT-328; D009943:Organophosphorus Compounds; D013467:Sulindac; D000518:Eflornithine