Comparison of tebufelone distribution in rat blood plasma and inflamed and noninflamed tissues following peroral and intravenous administration.
It is recognized that some acidic nonsteroidal antiinflammatory drugs (NSAIDs) accumulate in the synovial fluids of inflamed joints. The distribution of tebufelone, a member of the di-tert-butylphenol class of NSAIDs, between rat plasma and paw tissues (inflamed and noninflamed) was determined. Tebufelone was administered (doses providing 80% maximal effectiveness) perorally (po, 10 mg/kg) or intravenously (i.v., 0.5 mg/kg) to Sprague-Dawley rats just prior to injection of an inflammatory adjuvant (carrageenan) into one of the hind paws. Levels of the drug were measured in plasma, inflamed paws, and noninflamed paws at prescribed times postdosing by capillary gas chromatography/stable isotope dilution mass spectrometry. Tebufelone levels, as determined from areas under the curves of concentration versus time were sevenfold (po) and 11-fold (i.v.) higher in paw tissue than in plasma. Inflamed and noninflamed tissues have equal affinity for the drug. Calculated terminal-phase half-lives of tebufelone in paw tissue were similar following i.v. and po dosing (approximately 14 h) and equivalent to the plasma half-life of the drug after po dosing (approximately 10 h). The plasma half-life determined following i.v. dosing was considerably lower (2.8 h). The anti-inflammatory activity of tebufelone appears to correlate more closely with tissue distribution profiles than plasma drug levels at the dose levels examined.
Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45239-8707.
M J
MJ
Doyle
T H
TH
Eichhold
M E
ME
Loomans
R W
RW
Farmer
G R
GR
Kelm
D000284:Administration, Oral; D000480:Alkynes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002351:Carrageenan / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D010636:Phenols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000480:Alkynes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010636:Phenols; D002351:Carrageenan; C064268:tebufelone