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Characterization of the protein binding of non-steroidal anti-inflammatory drugs in synovial fluid


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Jack, DS 1990 , 'Characterization of the protein binding of non-steroidal anti-inflammatory drugs in synovial fluid', Coursework Master thesis, University of Tasmania.

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The clinical pharmacokinetic properties of NSAID's are markedly influenced by the
affinity and extent of their protein binding properties in plasma and synovial fluid.
Whilst the total level of NSAID is dependent upon concentration and affinity of local
protein, it is the unbound / free fraction that is the species which readily diffuses
between plasma and synovial fluid. The synovial fluid kinetics of the NSAlD's
have received remarkably little attention until recent years, despite the increasing
accumulation of evidence casting doubt on a consistent pharmacokinetic correlation
between plasma concentrations of NSAID's and respective analgesic / anti -
inflammatory activity. This study examined the effect of some physical and
environmental factors on the protein binding of piroxicam and ibuprofen in synovial
In this current work, the Amicon MPS-1 ultrafiltration device provided rapid and
consistent separation of unbound NSAID in synovial fluids and HSA solutions.
Radiolabelled piroxicam provided a convenient and relatively simple means of
measuring the free fraction of this drug in synovial fluid using this device, with a
coefficient of variation of 9.8%.
The 2-arylpropionic acids include some marketed and commonly prescribed
NSAID's. They possess a chiral centre, are stereospecific in action and may
undergo metabolic inversion from the inactive R-(-) to the active S-(+) enantiomer.
The prostaglandin inhibitory effect resides with the S-(+) enantiomer, yet with the
exception of S-(+) naproxen, these agents are generally administered as racemic mixtures. The extent of metabolic chiral inversion in man is variable and may be one
very important factor in explaining the variability in response to these agents.Despite
the fact that the enantiomers of the 2-arylpropionic acid NSAID's differ in
pharmacological properties, we are still witnessing articles in the literature that
generate data of a non stereospecific nature.
In order to characterize the protein binding of the enantiomers of the chiral NSAID's
(ibuprofen and ketoprofen) in synovial fluid, a GC/MS assay procedure was
developed that was capable of determining ibuprofen enantiomer concentrations of
2ng/mL with a coefficient of variation of 5_ 10.8% and 7.4% for s-ibuprofen and
r-ibuprofen respectively. The entire procedure (complete in a matter of minutes),
was in marked contrast to the more lengthy methods found in the literature. The
procedure was readily adaptable to allow resolution of ketoprofen enantiomers with
a similar degree of sensitivity.
The free fractions of piroxicam and ibuprofen enantiomers were found to be
markedly dependent upon their respective drug and associated albumin
concentrations in synovial fluid according to pre-determined physical conditions.
Binding of piroxicam was found to be independent of pH at concentrations of drug
and albumin typically found in synovial fluid. There were marked differences in the
extent of binding of ibuprofen enantiomers to human serum albumin (HSA)
solutions, "fatty acid - stripped" HSA solutions, and synovial fluid. The current
studies suggest that caution with interpretation of binding constants determined from
experimental data (in these and similar studies), is essential, as most of the
commonly calculated values are based on saturation functions such as those
described by Scatchard and Klotz. Consideration should also be given to alternative
mathematical functions when interpreting the results of non-saturated binding
studies. As synovial fluid is close to the target tissue where a NSAM's effect is exerted, it is
reasonable to expect its concentration in this fluid to be a better indicator of drug
activity in rheumatic disease than in plasma. However, before an attempt to
correlate synovial fluid NSAID concentration with clinical response can be made,
consideration of the physical and environmental parameters affecting the protein
binding of the whole class of these drugs in synovial fluid may be beneficial.

Item Type: Thesis - Coursework Master
Authors/Creators:Jack, DS
Keywords: Nonsteroidal anti-inflammatory agents, Synovial fluid
Copyright Holders: The Author
Copyright Information:

Copyright 1990 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).

Additional Information:

Includes bibliographical references (p. 105-116). Thesis (M.Pharm.)--University of Tasmania, 1990. Spine title: N.S.A.I.D. binding in synovial fluid

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