Similar maximum systemic but not local cyclooxygenase-2 inhibition by 50 mg lumiracoxib and 90 mg etoricoxib: a randomized controlled trial in healthy subjects.
OBJECTIVE
Once daily doses of 100-400 mg lumiracoxib have been proposed to inhibit local prostaglandin synthesis longer than systemic prostaglandin synthesis due to local accumulation in inflamed, acidic tissue. Lower, less toxic doses, however, might still achieve the clinical goal and merit further contemplation.


METHODS
In a randomized, double-blind, placebo-controlled, three-way cross-over study, 18 healthy men received, with an interval of 24 h, two oral doses of 50 mg lumiracoxib or for comparison, 90 mg etoricoxib, for which local tissue accumulation has not been claimed as therapeutic component. Systemic and local drug concentrations, assessed by means of subcutaneous in-vivo microdialysis, were related to COX-2 inhibiting effects, quantified as inhibition of prostaglandin ex-vivo production in whole blood as well as local tissue prostaglandin (PG) concentrations.


RESULTS
Twenty-four hours after the first dose, only etoricoxib was detectable in plasma and inhibited PGE2 production. In contrast, after the second dose, systemic PGE2 concentrations were significantly reduced by both coxibs, indicating similar maximum systemic effects of the selected doses. The local COX-2 inhibition by etoricoxib was most pronounced for PGD2. To the contrary, no indication was given of local inhibition of PG production by lumiracoxib at the dose tested.


CONCLUSIONS
Doses of 50 mg lumiracoxib and 90 mg etoricoxib produced similar maximum inhibition of systemic COX-2 function whereas 50 mg lumiracoxib was ineffective in producing local COX-2 inhibition. At a 50 mg dosage, lumiracoxib does not provide peripheral effects that outlast its systemic actions in therapies of rheumatic diseases such as osteoarthritis.
Institute of Clinical Pharmacology, Goethe University, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
Lisa
L
Felden
Carmen
C
Walter
Carlo
C
Angioni
Yannick
Y
Schreiber
Nils
N
von Hentig
Nerea
N
Ferreiros
Gerd
G
Geisslinger
Jörn
J
Lötsch
D000328:Adult; D016718:Arachidonic Acid / Q000032:analysis / Q000378:metabolism; D018592:Cross-Over Studies; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004008:Diclofenac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004311:Double-Blind Method; D000077613:Etoricoxib; D006801:Humans; D008297:Male; D011453:Prostaglandins / Q000032:analysis / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D011725:Pyridines; D013450:Sulfones; D004008:Diclofenac; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C473384:lumiracoxib; D000077613:Etoricoxib