Interactions between oxicams and membrane bilayers: an explanation for their different COX selectivity.

M Lúcio, H Ferreira, José L F C Lima, Salette Reis

Departamento de química Física, Faculdade de Farmácia da Universidade do Porto. Rua Aníbal Cunha, 164, 4050-047 Porto, Portugal.

Medicinal chemistry (Shāriqah (United Arab Emirates)) 2006 Sep

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Meloxicam was launched as a major new NSAID for the treatment of arthritis following extensive published research confirming its selectivity for COX-2. Several studies proposed possible explanations for its effectiveness and superior safety profile. The proposed theories included chemical structural relationships between meloxicam and other effective NSAIDs with low gastrointestinal toxic effects. However, other oxicams have similar chemical groups, but despite this, are not considered COX-2 selective drugs and exhibit less gastric tolerance. Hence, the aim of this work was to investigate the interactions between oxicams and biomembrane models as it could influence their resorption from the upper gastrointestinal tract and may affect their local gastromucosal tolerability. The partition of oxicams within membranes was determined by calculating their partition coefficients between liposomes and water. Moreover, their location within the bilayer was determined by fluorescence quenching. Finally, zeta-potential measurements were made to complete the information about the binding behaviour of the oxicams and steady-state anisotropy measurements were made to determine their induced perturbation in membrane structure. These studies proved that, in spite of structural similarities, oxicams present different interactions with membranes making possible a virtual division of the class in two groups. Tenoxicam and piroxicam known as COX-1 inhibitors demonstrated higher partition capacity in liposomes/water systems together with a smaller ability to change the membrane fluidity and surface potential. In contrast lornoxicam and meloxicam, which demonstrated activity against COX-2, have revealed smaller partition capacity in liposomes/water systems together with a higher ability to change the membrane fluidity and surface potential.

Citation

M Lúcio, H Ferreira, José L F C Lima, Salette Reis. Interactions between oxicams and membrane bilayers: an explanation for their different COX selectivity. Medicinal chemistry (Shāriqah (United Arab Emirates)). 2006 Sep;2(5):447-56