Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac.

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Citation

Hinz B, Rau T, Auge D, Werner U, Ramer R, Rietbrock S, Brune K

Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac.

Clin Pharmacol Ther. 2003 Sep;74(3):222-35.

PubMed ID
12966366 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
DiclofenacProstaglandin G/H synthase 1ProteinHumans
Yes
Inhibitor
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