Recent pharmacodynamic and pharmacokinetic findings on oxaprozin
Oxaprozin has proven a safe and effective treatment for arthritic conditions. It has a low incidence of gastrointestinal side effects making it a particularly attractive therapy. Being an unselective COX-1 and COX-2 inhibitor the drug may have advantages in more effective pain relief related to both COX-1 as well as COX-2 effects. We have investigated the pharmacology of oxaprozin on (a) the biochemical components of joint destruction in vitro, and (b) the pharmacokinetic interactions of this drug with albumin in vitro in which drug interactions are modelled by competitive binding of the drug with endogenous ligands or drugs that are commonly prescribed with NSAIDs. The latter in vitro pharmacokinetic study can be considered as a basis for understanding both safety and therapeutic activity of the drug. Among the major effects of oxaprozin (10-100 μM) observed on components of joint destruction was (a) the inhibition of the production of interleukin-1β (IL-1β) from pig synovial tissues in organ culture and IL-1β, IL-6 and IL-8, as well as tumour necrosis factor-α (TNFα) from THP-1 mononuclear cells at 50-100 μM. Oxaprozin (1.0-100 μM) did not affect NO production from porcine synovial tissue, whereas indomethacin and nimesulide reduced production of NO. Oxaprozin did not exacerbate the IL-1β and/or TNFα-induced proteoglycan destruction in pig or bovine cartilage in organ culture as observed with indomethacin and aspirin. Radiolabelled oxaprozin accumulated in cartilage to a much greater extent than observed with other NSAIDs. This may be a particular advantage in enabling expression of cartilage protective effects of the drug. Albumin binding of [14C]oxaprozin (10 μM) in vitro was unaffected by other NSAIDs (e.g., aspirin, diclofenac, ibuprofen, paracetamol, salicylate), a range of commonly co-prescribed drugs (e.g., atenolol, clonidine, cromolyn, diphenhydramine, furosemide, ketotifen, salbutamol, prednisolone, theophylline), endogenous steroids (e.g., oestradiol, progesterone) or other agents (e.g., caffeine) at concentrations of 40 μM. The free concentrations of oxaprozin were, however, increased slightly by the same concentrations of warfarin, prednisolone, diazepam and captopril. In contrast, the binding of oxaprozin to free-fatty acid depleted albumin was only appreciably affected by captopril and caffeine. The free oxaprozin was slightly increased by zinc and copper ions (which are increased in rheumatic conditions) in normal as well as fatty acid-free albumin. Tryptophan release from albumin, which has a role in central analgesic actions of anti-rheumatic drugs by enhancing CNS turnover of 5-hydroxytryptamine (serotonin), was increased by 50-100 μM oxaprozin, as well as other NSAIDs. This indicates that serotonergic activation could also contributed to the analgesic properties of oxaprozin like that of other NSAIDs. These studies indicate that the potentially-significant pharmacodynamic actions of oxaprozin in arthritic joints may involve inhibition of the release of pro-inflammatory cytokines from inflamed synovium and relatively high rate of drug uptake into inflamed joints. Analgesia, in addition to being a consequence of prostaglandin inhibition, may be initiated by release of albumin-bound tryptophan and uptake into the brains leading to activate serotonergic pathways of pain suppression. Oxaprozin is only slightly affected pharmacokinetically by some co-prescribed drugs or patho-physiologic metal ions but these effects may be of limited clinical consequence principally as oxaprozin has a relatively long plasma elimination half-life (50-60 h) and any small increase in free concentrations of the drug in circulating plasma increases elimination of the drug.
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