title: Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac.
abstract: OBJECTIVE
  The mechanism of action of aceclofenac is currently unclear. This study investigated whether biotransformation to metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) contributes to inhibitory effects on the cyclooxygenase (COX) isozymes in vitro and ex vivo.
  
  
  METHODS
  In vitro investigations were performed with human whole blood and human blood monocytes. A randomized crossover study was performed in volunteers receiving 100 mg aceclofenac or a sustained-release resinate formulation of 75 mg diclofenac to assess the pharmacokinetics and the ex vivo inhibition of COX-1.
  
  
  RESULTS
  In short-term in vitro assays, neither aceclofenac nor 4'-hydroxy-aceclofenac affected COX-1 or COX-2, whereas diclofenac and 4'-hydroxy-diclofenac inhibited both isoforms. In long-term in vitro assays, aceclofenac and 4'-hydroxy-aceclofenac suppressed both COX isoforms. However, this inhibition was paralleled by a conversion to diclofenac and 4'-hydroxy-diclofenac, respectively. Maximal plasma concentrations of diclofenac after oral administration of aceclofenac (0.39 micromol/L) or diclofenac (1.28 micromol/L) were sufficient for a greater than 97% inhibition of COX-2 (50% inhibitory concentration, 0.024 micromol/L) and a 46% (aceclofenac treatment) or 82% inhibition (diclofenac treatment) of COX-1 (50% inhibitory concentration, 0.43 micromol/L). Moreover, ex vivo COX-1-dependent thromboxane B(2) synthesis was inhibited significantly less by aceclofenac than by diclofenac.
  
  
  CONCLUSIONS
  Inhibition of COX isozymes by aceclofenac requires conversion into diclofenac. Although 100 mg aceclofenac yielded diclofenac concentrations substantially lower than 75 mg diclofenac, these were sufficient for a sustained block of COX-2 but caused a minor and shorter inhibition of COX-1 than 75 mg diclofenac. In conclusion, both COX-1-sparing and COX-2-inhibitory actions of aceclofenac may rest in its limited but sustained biotransformation to diclofenac.
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany. hinz@pharmakologie.uni-erlangen.de
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rau
authors.forename: Daniel
authors.initials: D
authors.lastname: Auge
authors.forename: Ulrike
authors.initials: U
authors.lastname: Werner
authors.forename: Robert
authors.initials: R
authors.lastname: Ramer
authors.forename: Stephan
authors.initials: S
authors.lastname: Rietbrock
authors.forename: Kay
authors.initials: K
authors.lastname: Brune
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001711:Biotransformation; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D004008:Diclofenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C056498:aceclofenac