title: Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety.
abstract: OBJECTIVE
  Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs).
  
  
  METHODS
  The CYP/FMO-catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach.
  
  
  RESULTS
  The CYP isoforms catalyse the oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac respectively. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho-sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho-sulindac may be due to their greater lipophilicity, a key parameter for CYP binding.
  
  
  CONCLUSIONS
  CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety.
authors.affiliation: Department of Medicine, Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794-8173, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Chi C
authors.initials: CC
authors.lastname: Wong
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Cheng
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Panayiotis P
authors.initials: PP
authors.lastname: Constantinides
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D010755:Organophosphates / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013467:Sulindac / Q000378:metabolism*
chemical_list: C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010755:Organophosphates; D011994:Recombinant Proteins; D013467:Sulindac; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D007052:Ibuprofen