Can non-steroidal anti-inflammatory drugs act as metalloproteinase modulators? An in-vitro study of inhibition of collagenase activity.
The in-vitro effects of some non-steroidal anti-inflammatory drugs and some analgesic drugs on collagenase activity were studied by use of a self-quenched fluorogenic esapeptide as substrate. The increased fluorescence signal arising as a result of peptide cleavage by collagenase was recorded and related to the inhibitory potency of the drugs. The effective concentrations in collagenase modulation were also correlated with the levels of the drugs in the plasma and synovial fluids of patients receiving therapeutic doses. Six of the tested drugs, nimesulide, piroxicam, tolmetin, meloxicam, sulindac and sodium meclofenamate, inhibited enzyme activity with IC50 values (concentrations resulting in 50% inhibition) ranging from 1.9 to 28.2 microM and Ki (apparent inhibition constant) ranging from 0.83 to 21.8 microM. Much of the activity was restored after dialysis of the enzyme-drug complex, demonstrating the reversibility of the effect. Although these results indicate that some anti-inflammatory drugs could modulate enzymatic activity involved in the degradation of the extracellular matrix, their possible pharmacological involvement as collagenase inhibitors in collagen degradative diseases remains to be assessed by clinical studies.
Cattedra di Farmacologia Medica, Facoltà di Medicina e Chirurgia, Università di L'Aquila, Italy.
A
A
Barracchini
N
N
Franceschini
G
G
Amicosante
A
A
Oratore
G
G
Minisola
G
G
Pantaleoni
A
A
Di Giulio
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D013582:Synovial Fluid / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases