Clinical pharmacology of oxicams: new insights into the mechanisms of their dose-dependent toxicity.
Six oxicams, sudoxicam, isoxicam, piroxicam, tenoxicam, meloxicam and lornoxicam, were compared in an attempt to understand why, despite close chemical structures, two of them were associated with an increased risk of toxicity in patients. Different factors have been revealed which may explain these differences. A weak association constant to human serum albumin (HSA), together with a high plasma concentration, favours a rapid increase in unbound concentration (Cu) when total plasma concentration rises (peak of absorption). Pathological states may enhance this increase when both HSA plasma concentration is decreased and free fatty acid concentrations are increased. However, the main cause of toxicity may be the existence in some subjects of HSA natural mutants whose ability to bind oxicams is markedly lower than normal.
Albengres
E
E
Centre Régional de Pharmacovigilance de Paris--Val de Marne, Centre Hospitalier Intercommunal, Créteil, France.
Urien
S
S
Barre
J
J
Nguyen
P
P
Bree
F
F
Jolliet
P
P
Tillement
J P
JP
Tsai
R S
RS
Carrupt
P A
PA
Testa
B
B
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D012307:Risk Factors; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012709:Serum Albumin