Regarding celecoxib, the only pharmacokinetic study on synovial fluids to our knowledge is that of Hunter et al. Celecoxib was determined in all synovial fluids one hour after per os administration, while synovial concentrations of the drug were constantly less than those in serum except in synovial fluid samples drawn 24 hours after the last p. Moreover, in none of these studies correlations of penetration or pharmacokinetics in synovial fluid, with NSAIDs effect on pain VAS have been reported.
In the present study, the presence of target molecules in the clinical sample was certified with the analysis of samples by Q-TOF-MS. Recent developments in this technology offer features that enhance drug metabolism and pharmacokinetic analysis, providing full product spectra, high specificity and sensitivity.
This diversity in the penetration capability can be attributed to their different chemical structure as mentioned in the introduction. Regarding celecoxib, an interesting study of Hunter et al. During first pass from the liver a proportion of the drug is metabolized by the respective enzyme and the rest, which is the active part, enters the systemic circulation.
In an in vitro study it has been found that there are two different cytochrome P CYP phenotypes in humans: the one that metabolizes slowly and the one that metabolizes fast, 16 and several polymorphisms of the CYP2C9 which is the main enzyme that metabolizes celecoxib.
Celecoxib has been reported to inhibit isomorphic CYP2D6 in humans. Etoricoxib is metabolized by a different enzyme. Moreover, it could be that an unknown celecoxib metabolite contributes to its penetration in the joint fluid. Our finding that celecoxib was not detected in all synovial fluids, probably relates either to the lower ability of its molecule to penetrate the synovial membrane, or a property of its molecule to penetrate it on a delayed fashion.
We measured the concentrations of the study drugs, both in serum and synovial fluid, at a time point respectively to their C max in blood according to their known pharmacokinetics 39 which are: 1 hour after etoricoxib dose, and 3 hours after the morning dose of celecoxib. In most patients suffering from rheumatic diseases, clinical response to most NSAIDs has little correlation with their plasma concentration.
It has been reported in some studies that synovial fluid of patients with arthritis may behave as a peripheral compartment and thus there is a lag of time between NSAIDs' systematic distribution. Scott et al. They hypothesized that either a significant proportion of the drug was distributed in another compartment related to pain, such as the joint, or that an active metabolite was delayed in plasma. In this same study it was found that synovial fluid C max were gained hours later than plasma C max , and surpassed plasma C max 5 hours after p.
Thus, synovial fluid concentrations were higher than plasma concentrations for 28 hours and therapeutic results of lumiracoxib lasted more than that expected from its plasma pharmacokinetics. These results are in agreement with Bingham et al.
In these studies, there was no statistically significant difference on pain control between the 2 drugs. In our study, we used the same dose for celecoxib mg daily but a triple dose for etoricoxib 90mg daily which is the recommended dose for inflammatory arthritis and this might explain our results.
As mentioned in the introduction, etoricoxib has better bioavailability than celecoxib, the celecoxib metabolites are totally inactive, whereas etoricoxib metabolites may have a weak activity as COX-2 inhibitors.
Moreover, the enzymes that metabolize these two coxibs are different. We found no statistically significant correlation between VAS changes and the penetration index of the synovial fluid for the 2 study drugs.
Moreover, we measured concentrations of the drugs in synovial fluid and serum from only one time point, respective to the theoretical serum C max , which it is known that is different from the synovial fluid C max. On the other hand, PI was calculated based on the concentrations of the original compound and not its metabolites.
Celecoxib metabolites are inactive on COX-2, but etoricoxib metabolites have a weak action. Additionally, we don't know their actions on substance P, cytokine and other pain-related mediators. We should keep in mind that VAS although easy, and popular is a subjective pain measure, 49 and, therefore, correlations of pain VAS withPI are not objective. Am J Gastroenterol. Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract.
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Next: Conference Highlights. Jun 15, Issue. Cyclooxygenase-2 Enzyme Inhibitors: Place in Therapy. TABLE 1. TABLE 2. Celecoxib Celebrex : Selected Potential Drug Interactions Cytochrome PC9 inhibitors that may increase serum concentrations of celecoxib Amiodarone Cordarone Chloramphenicol Chloromycetin Cimetidine Tagamet Fluconazole Diflucan Fluvastatin Lescol Omeprazole Prilosec Zafirlukast Accolate Drugs metabolized by cytochrome PD6 whose serum concentrations may be increased by celecoxib Antiarrhythmics: flecainide Tambocor , encainide Enkaid , mexiletine Mexitil Antidepressants: Selective serotonin reuptake inhibitors: fluoxetine Prozac , paroxetine Paxil , sertraline Zoloft Tricyclic antidepressants: amitriptyline Elavil , imipramine Tofranil , nortriptyline Pamelor Venlafaxine Effexor Antipsychotics: haloperidol Haldol , perphenazine Trilafon , risperidone Risperdal Beta blockers: metoprolol tartrate Lopressor , propranolol Inderal , timolol Betimol Opiates: codeine, dextromethorphan Information from McEboy GK, ed.
TABLE 3. TABLE 4. TABLE 5. Read the full article. Get immediate access, anytime, anywhere. Choose a single article, issue, or full-access subscription. Earn up to 6 CME credits per issue. Purchase Access: See My Options close. Best Value! Racial differences in drug disposition and pharmacokinetic changes in the elderly have been reported for celecoxib. Celecoxib does not appear to interact with warfarin, ketoconazole or methotrexate; however, clinically significant drug interactions with fluconazole and lithium have been documented.
As celecoxib is metabolised by CYP2C9, increased clinical vigilance is required during the coadministration of other substrates or inhibitors of this enzyme.
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