Pharmacokinetics of celecoxib in the presence and absence of interferon-induced acute inflammation in the rat: application of a novel HPLC assay.
OBJECTIVE
Celecoxib (CEL) is a relatively new cyclooxygenase-2 specific inhibitor nonsteroidal anti-inflammatory drug with low incidents of the toxic side effects. We developed and validated an HPLC assay for CEL and delineated pharmacokinetics of the drug in the rat in the presence and absence of inflammation.


METHODS
Rat plasma (0.1 mL plasma) was spiked with CEL and ibuprofen as internal standard. The solution was acidified and constituents were extracted with isooctane-isopropanol (95:5). The organic solvent was separated, evaporated and the residue was dissolved in the HPLC mobile phase [acetonitrile-water-acetic acid-triethylamine (47:53:0.1:0.03)]. The HPLC system consisted of an auto-injector, an isocratic pump, a 10 cm C(18) analytical column packed with 5-microm of reversed-phase particles, a UV detector set at 254 nm, and an integrator. Control adult male Sprague-Dawley rats were dosed with CEL [5 mg/kg i.v. (n=8), p.o. (n=6) or i.p. (n=3)]. Acute inflammation was brought about by two (12 and 1 h pre-CEL) s.c. injection of 50,000IU/200 microL interferonalpha2a. Inflamed rats (n=6) received 5 mg oral CEL. Serial blood samples were collected via a inserted catheter at the right jugular vein, and plasma samples were analyzed for CEL.


RESULTS
The assay yielded linear response within the examined ranges of 20-1000 ng/mL and 1-100 microg/mL (r(2)>0.99) with an extraction efficiency of >70%, intra- and inter-day variability of <10% and accuracy of >90%. In control rats, CEL had an oral bioavailability of 0.59 due mainly to presystemic hepatic metabolism. A multi-compartmental disposition kinetics with an average terminal t(1/2) of 2.8 +/- 0.7 h, and volume of distribution of 2.3 +/- 0.6 L/kg were found. Acute inflammation had no significant effect on the pharmacokinetics of CEL, although a trend towards increased plasma concentration was noticed.


CONCLUSIONS
The validated assay has sufficient accuracy and precision for pharmacokinetic studies of CEL in the rat. The lack of change in CEL pharmacokinetics after acute inflammation maybe due to 1) insensitivity of its metabolic system to the acknowledged inhibitory effect of inflammation, and/or 2) the relatively low pre-systemic metabolism of the drug.
Guirguis
M S
MS
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Sattari
S
S
Jamali
F
F
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D000068579:Celecoxib; D002851:Chromatography, High Pressure Liquid; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007372:Interferons / Q000494:pharmacology*; D008297:Male; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; D007372:Interferons; D000068579:Celecoxib