Articular diffusion of meloxicam after a single oral dose: relationship to cyclo-oxygenase inhibition in synovial cells.
OBJECTIVE
To investigate the distribution of meloxicam in the human knee joint and to compare it with the inhibition of cyclo-oxygenase (COX) activity in synovial cells.


METHODS
Prospective pharmacokinetic study and in vitro laboratory investigation.


METHODS
42 male and female patients aged 26 to 85 years hospitalised for rheumatic disease and requiring a diagnostic and/or therapeutic knee puncture.


METHODS
After a single oral dose of meloxicam 15mg, synovial fluid and blood samples were collected once per patient at various intervals after administration. Meloxicam concentrations were determined by a validated high performance liquid chromatography assay, protein binding by equilibrium dialysis, and pharmacokinetic parameters were calculated by noncompartmental analysis from the mean drug concentration-time profiles. The inhibitory effect of meloxicam on COX activity was investigated separately in unstimulated or interleukin-1beta-stimulated human synovial cells from osteoarthritic patients.


RESULTS
Meloxicam was found in synovial fluid at the earliest sampling time (1 hour). Peak concentrations were reached approximately 6 hours postdose in both plasma (842 microg/L) and synovial fluid (320 microg/L). A plateau was observed after the distribution phase (6 hours), corresponding to a constant ratio of drug concentration between synovial fluid and plasma of about 0.47. This ratio was higher in patients with acute inflammation (0.58) than in those with no inflammation (0.38). Meloxicam was extensively bound to protein, mainly to serum albumin. The area under the drug concentration-time curve (AUC) in plasma was more than 2.5 times that in synovial fluid. The AUC for free meloxicam was similar in plasma and synovial fluid. The 50% inhibitory concentrations (IC50) for basal and stimulated COX activity in human synovial cells were 33.7 nmol/L (11.8 microg/L) and 2.0 nmol/L (0.70 microg/L), respectively. The free concentration of meloxicam in synovial fluid was higher than the IC50 for stimulated COX activity from 6 to 36 hours postdose.


CONCLUSIONS
On the basis of free synovial concentrations and the IC50 for stimulated COX activity, meloxicam is expected to have a long duration of action. Inhibition of COX activity is expected to be more marked in inflamed synovium compared with non-inflamed synovium.
Lapicque
F
F
Physiopathologie et Pharmacologie Articulaires, UMR 7561, Centre National de la Recherche Scientifique-Université Henri Poincaré Nancy 1, Vandoeuvre les Nancy, France.
Vergne
P
P
Jouzeau
J Y
JY
Loeuille
D
D
Gillet
P
P
Vignon
E
E
Thomas
P
P
Velicitat
P
P
Türck
D
D
Guillaume
C
C
Gaucher
A
A
Bertin
P
P
Netter
P
P
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D004058:Diffusion; D005260:Female; D006801:Humans; D007719:Knee Joint / Q000378:metabolism*; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged; D011446:Prospective Studies; D011485:Protein Binding; D013582:Synovial Fluid / Q000378:metabolism; D013843:Thiazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013843:Thiazines; D013844:Thiazoles; D000077239:Meloxicam