The effects and metabolic fate of nitroflurbiprofen in healthy volunteers.
OBJECTIVE
Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are a new class of cyclooxygenase (COX) inhibitors. To investigate whether these drugs actually release nitric oxide (NO), we labeled the nitroxy group of nitroflurbiprofen with nitrogen 15 to determine the metabolic fate of this compound in humans.


METHODS
Six healthy volunteers who fasted were given an oral dose of 15 N-nitroflurbiprofen (100 mg). Samples of blood, urine, and gastric headspace gas were taken over a 24-hour period to determine the levels of nitroflurbiprofen, flurbiprofen, total nitrate/nitrite, 15 N-nitrate/nitrite, COX activity, and gastric NO. In a crossover study (1 week apart), a further 6 healthy volunteers who fasted were given an oral dose of nitroflurbiprofen (100 mg) or flurbiprofen (65 mg) and levels of gastric NO were determined.


RESULTS
Nitroflurbiprofen was undetectable in the systemic circulation. Levels of 15 N-nitrate/nitrite (5.2% +/- 1.5% enrichment) and flurbiprofen (2.4 +/- 0.7 microg/mL) peaked at 4 hours in the plasma and gradually decreased thereafter. In unstimulated blood, the plasma levels of thromboxane B 2 (COX-1 activity) were 2 to 3 ng/mL, and after calcium ionophore stimulation, large amounts of thromboxane B 2 were produced (112 +/- 31 ng/mL). Prostaglandin E 2 was undetectable in unstimulated blood. After lipopolysaccharide stimulation, the plasma levels of prostaglandin E 2 increased to 15 +/- 4 ng/mL. The metabolite flurbiprofen inhibited plasma COX-1 activity for the duration of the study period (maximum inhibition at 4 hours), whereas COX-2 activity recovered after 6 hours. In the crossover study, levels of gastric NO were higher in subjects given nitroflurbiprofen, when compared with those given flurbiprofen. (The area under the curve for gastric NO was 435 +/- 107 ppm . h versus 305 +/- 94 ppm . h [95% confidence interval of the difference, 89-172 ppm . h; P < .001]).


CONCLUSIONS
Nitroflurbiprofen was undetectable in the systemic circulation, suggesting metabolism to 15 N-nitrate/nitrite and flurbiprofen in the presystemic circulation. Levels of gastric NO were significantly higher after ingestion of nitroflurbiprofen than flurbiprofen.
William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry.
Paula
P
Zacharowski
Kai
K
Zacharowski
Clare
C
Donnellan
Atholl
A
Johnston
Ivana
I
Vojnovic
Pablo
P
Forte
Piero
P
Del Soldato
Nigel
N
Benjamin
Sharon
S
O'Byrne
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D005260:Female; D005480:Flurbiprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D005750:Gastric Juice / Q000737:chemistry / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D009587:Nitrogen Isotopes; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009587:Nitrogen Isotopes; C095631:nitroflurbiprofen; D009569:Nitric Oxide; D005480:Flurbiprofen