Naproxen Concentrations in Serum Synovial Fluid, and Synovium

Jalava, S; Saarimaa, H. A.; Anttila, Markku; Sundquist, Hannah

doi:10.3109/03009747709095441

Cited by 29 publications

(6 citation statements)

References 17 publications

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“…Studies of the first type have shown considerable joint localization of sodium naproxen (Bruno et al 1988;Dougados et al 1986;Franssen et al 1986;Gougeon et al 1989;Jalava et al 1977;Runkel et al 1972Runkel et al , 1973Sevelius et al 1980;Upton et al 1984) with a half-life of approximately 31 h. The present study is of the second type and shows that, at steady state, total residual concentrations are similar in plasma and in synovial fluid. Studies of the first type have shown considerable joint localization of sodium naproxen (Bruno et al 1988;Dougados et al 1986;Franssen et al 1986;Gougeon et al 1989;Jalava et al 1977;Runkel et al 1972Runkel et al , 1973Sevelius et al 1980;Upton et al 1984) with a half-life of approximately 31 h. The present study is of the second type and shows that, at steady state, total residual concentrations are similar in plasma and in synovial fluid.…”

Section: Discussionsupporting

confidence: 56%

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid

Bertin

Lapicque

Payan

et al. 1994

Eur J Clin Pharmacol

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Twelve patients suffering from rheumatoid arthritis and having swollen knees were treated with 1.1 g/day of sodium naproxen administered in one dose, daily for 5 days. The 72-h wash-out period was verified by the absence of any nonsteroidal anti-inflammatory drug using a HPLC screening. Blood and synovial fluid samples were drawn just before treatment and 24 h after the last dose. Eicosanoids (PGE2, 6-keto-PGF1 alpha, TXB2, LTB4, LTC4) in synovial fluid were determined by immunoenzymatic assays. In plasma and synovial fluid, hyaluronic acid was assayed by radiometric assay and sodium naproxen by HPLC. Free drug was determined by equilibrium dialysis. Statistical analysis used nonparametric tests. Pain relief (evaluated on a visual scale), morning stiffness, and scores on the Lee and Ritchie indices all decreased significantly, as did PGE2 and LTB4 concentrations. The decrease in 6-keto-PGF1 alpha and TXB2 was not significant. No significant change was found for LTC4 and hyaluronic acid. Total concentrations of sodium naproxen were equivalent in plasma (16.1 micrograms.ml-1) and synovial fluid (18.9 micrograms.ml-1). Free fractions were significantly higher in synovial fluid (0.14%) than in plasma (0.11%), as shown by binding of the drug to human serum albumin, at various protein concentrations. Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and in the Lee index score, correlated with the free concentration of naproxen in synovial fluid.

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Section: Discussionsupporting

confidence: 56%

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid

Bertin

Lapicque

Payan

et al. 1994

Eur J Clin Pharmacol

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“…Concentrations of drugs in synovial tissue homogenates and synovial fluid have been contrasted in 2 studies examining the pharmacokinetics of non-steroidal anti-inflammatory drugs (Jalava et al, 1977;Laine et al, 1975). Synovial tissue concentrations of benorylate, a lipophilic agent, were equivalent to synovial fluid concentrations, while synovial tissue concentrations of naproxen were 60% of concurrent synovial fluid values.…”

Section: Discussionmentioning

confidence: 98%

Antirheumatic Drug Concentrations in Human Synovial Fluid and Synovial Tissue

Wallis

Simkin²

1983

Clinical Pharmacokinetics

108

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Antirheumatic drug concentrations have been measured in human synovial fluid and synovial tissue, and provide insights on: (1) extravascular pharmacokinetics; (2) articular pathophysiology; and (3) the factors which modify drug levels in inflamed tissues. Concentrations of free drug in synovial fluid and plasma are the same in all conditions except rheumatoid and infectious arthritis, where the most severely afflicted joints may contain lower synovial fluid drug concentrations. This finding may be relevant to the chronicity and intractability of chronic arthritis. After single-dose therapy and a characteristic 'equilibration time', higher concentrations are found in synovial fluid than in plasma - a phenomenon which results from relative drug sequestration across the trans-synovial diffusion barrier away from the organs of elimination. Studies of oral, parenteral, topical and intra-articular antirheumatic drug therapy are reviewed, and recommendations are made for the conduct of future studies.

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“…Other studies merely described the nonlinear exposures of NPX in acute inflammation (Josa et al, 2001;Krekels et al, 2011). The clinical efficacy of NPX appeared to be better correlated with its unbound concentrations in synovial fluid (SF), as synovium is the proposed site of action in RA (Jalava et al, 1977;Netter et al, 1989;Bertin et al, 1994;Day et al, 1995). In spite of this literature, there are limited quantitative insights into the PK/PD relationships of NPX in chronic inflammatory conditions such as RA.…”

Section: Introductionmentioning

confidence: 99%

Modeling Sex Differences in Pharmacokinetics, Pharmacodynamics, and Disease Progression Effects of Naproxen in Rats with Collagen-Induced Arthritis

DuBois

Almon

et al. 2017

Drug Metab Dispos

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Naproxen (NPX) is a frequently used nonsteroidal anti-inflammatory drug for rheumatoid arthritis (RA). Lack of quantitative information about the drug exposure-response relationship has resulted in empirical dosage regimens for use of NPX in RA. Few studies to date have included sex as a factor, although RA predominates in women. A pharmacokinetic, pharmacodynamic, and disease progression model described the anti-inflammatory effects of NPX in collagen-induced arthritic (CIA) male and female rats. Three groups of rats were included for each sex: healthy animals, CIA controls, and CIA rats given a single 50-mg/kg dose of NPX intraperitoneally. Paw volumes of healthy rats indicated natural growth, and disease status was measured by paw edema. An innovative minimal physiologically based pharmacokinetic (mPBPK) model incorporating nonlinear albumin binding of NPX in both plasma and interstitial fluid (ISF) was applied. Arthritic rats exhibited lower plasma and ISF albumin concentrations and reduced clearances of unbound drug to explain pharmacokinetic profiles. The unbound ISF NPX concentrations predicted by the mPBPK model were used as the driving force for pharmacological effects of NPX. A logistic growth function accounting for natural paw growth and an indirect response model for paw edema and drug effects (inhibition of ) was applied. Female rats showed a higher incidence of CIA, earlier disease onset, and more severe symptoms. NPX had stronger effects in males, owing to higher unbound ISF NPX concentrations and lower IC values. The model described the pharmacokinetics, unbound NPX in ISF, time course of anti-inflammatory effects, and sex differences in CIA rats.

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Naproxen Concentrations in Serum Synovial Fluid, and Synovium

Cited by 29 publications

References 17 publications

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid

Antirheumatic Drug Concentrations in Human Synovial Fluid and Synovial Tissue

Modeling Sex Differences in Pharmacokinetics, Pharmacodynamics, and Disease Progression Effects of Naproxen in Rats with Collagen-Induced Arthritis

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