The reactions of oxicam and sulfoanilide non steroidal anti-inflammatory drugs with hypochlorous acid: determination of the rate constants with an assay based on the competition with para-aminobenzoic acid chlorination and identification of some oxidation products.
Hypochlorous acid (HOCl) is an oxygen-derived species involved in physiological processes related to the defence of the organism that may cause adverse effects when its production is insufficiently controlled. In order to examine its reactivity with potential scavenging molecules from the non steroidal anti-inflammatory drugs (NSAIDs) family, a competition assay based on para-aminobenzoic acid (PABA) chlorination was developed. The original optimised in vitro fluorimetric procedure offered the possibility to determine rate constants (ks) for the reaction with HOCl in physiologically relevant conditions. The specificity of the system was improved by a liquid chromatography (LC) which allows the separation of the drugs and their oxidation products. After determination of the rate constant for PABA chlorination by HOCl (mean +/- SD in M(-1) s(-1): 4.3 +/- 0.3 x 10(3)), the applied mathematical model for a chemical competition permits to obtain linear curves from competition studies between several NSAIDs and PABA. Their slopes provided the following rate constants for the different studied drugs: tenoxicam: 4.0 +/- 0.7 x 10(3), piroxicam: 3.6 +/- 0.7 x 10(3), lornoxicam: 4.3 +/- 0.7 x 10(3), meloxicam: 1.7 +/- 0.3 x 10(4), nimesulide: 2.3 +/- 0.6 x 10(2). Meloxicam therefore reacted significantly faster than the other oxicams and nimesulide, which is the weakest scavenger of the studied series. The identification of some of the oxidation products by NMR or MS permitted to explore the reaction mechanism and to examine some aspects of the structure/activity relationships for the molecules of the same chemical family.
Van Antwerpen
P
P
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Université Libre de Bruxelles, Bld du Triomphe, Campus Plaine 205/5, B-1050 Brussels, Belgium.
Dubois
J
J
Gelbcke
M
M
Neve
J
J
D010129:4-Aminobenzoic Acid / Q000737:chemistry*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D001667:Binding, Competitive; D006997:Hypochlorous Acid / Q000737:chemistry*; D007700:Kinetics; D016014:Linear Models; D000077239:Meloxicam; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry*; D013843:Thiazines / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D006997:Hypochlorous Acid; C059451:lornoxicam; D010129:4-Aminobenzoic Acid; C012655:nimesulide; D000077239:Meloxicam; C032801:tenoxicam