Exploration in vitro et ex vivo du pouvoir inhibiteur des anti-inflammatoires non stéroïdiens vis-à-vis des iso-enzymes de la cyclooxygénase

Abstract : A review of the literature shows that whether the inhibitory potency of nonsteroidal anti-inflammatory drugs on cyclooxygenase (COX) iso-enzymes, when given therapeutically in humans, can be predicted from their in vitro concentration-response curves using the whole blood assay is unknown. Therefore, wedetermined the inhibition of blood COX iso-enzymes in 24 healthy male volunteers aged 20 to 27 years, in vitro before any drug intake and ex vivo after single and repeated intake of either 7.5 mg meloxicam once, 400 mg ibuprofen t.i.d. or 75 mg diclofenac SR once, taken in a randomized cross-over design. Production of thromboxane B2 (TxB2) during clotting and of prostaglandin E2 (PGE2) during endotoxin exposure served as indicators of platelet COX-1 and monocyte COX-2 activity respectively. Drug were determined in plasma by HPLC, with a chiral separation of ibuprofen and free fractions after equilibrium dialysis. lntra-subject variation for COX-1 and COX-2 at baseline was at 26 ± 18 % and 18 ± 13 % respectively and inter-subject variation at 39%.and 36% respectively. The ratios of ICsos and, at best, of IC80s revealed diclofenac and meloxicam as selective COX-2 inhibitors and ibuprofen as a preferential COX-1 inhibitor in vitro. However, after oral intake, ibuprofen inhibited ex vivo COX-2 by 80 % whereas diclofenac inhibited COX-1 by 70.%. Meloxicam inhibited COX-1 from 30 to 55 % depending on the repetition of the dose and increase in plasma concentrations. Using in vitro dose-response curves, the in vivo inhibitory potency of diclofenac was estimated adequately from its circulating concentration ([- 0.18;0.21] for COX-1 and [- 0.13;-0.03] for COX-2) but this was not the case for ibuprofen on COX-2 ([- 0.14;0.27]) and meloxicam on COX-1 ([0.31; 1.05]). The limited predictability of the system was not improved through considering the unbound fraction of the drugs or the variable chiral inversion of ibuprofen. ln conclusion, assessment of COX-2 selectivity based on in vitro studies and pharmacological modelling has a limited clinical relevance and investigation of COX selectivity at therapeutic plasma concentrations of NSAIDs using the ex vivo whole blood assay is required.
Mots-clés : Isoenzymes
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Hubert Blain. Exploration in vitro et ex vivo du pouvoir inhibiteur des anti-inflammatoires non stéroïdiens vis-à-vis des iso-enzymes de la cyclooxygénase. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2002. Français. ⟨NNT : 2002NAN11304⟩. ⟨tel-01754434⟩

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