Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac.
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.
Hinz
Burkhard
B
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany. hinz@pharmakologie.uni-erlangen.de
Rau
Thomas
T
Auge
Daniel
D
Werner
Ulrike
U
Ramer
Robert
R
Rietbrock
Stephan
S
Brune
Kay
K
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
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