Correlation plasma levels, NSAID and therapeutic response

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Abstract
A regular control of nonsteroidal anti-inflammatory drug (NSAID) plasma levels may be useful (i) to avoid undesirable side-effects (ii) to monitor therapeutic progress (iii) to see if patients are complying with their prescription. Trying to establish a relationship between the plasma concentration of a drug and its clinical effects requires a few prerequisites which may or may not be fulfilled according to the NSAID (e.g. a drug acting by itself, a reversible action, no tolerance to the drug, a highly specific and sensitive enough analytical method of the drug, similar free drug concentrations in the plasma and at the receptor sites,...), the most important of them-which is also probably the most difficult to fulfil in the case of rheumatic diseases-being that the clinical effect of the drug must be easily measured. In fact, the evidence for a good correlation between clinical effects and drug plasma levels are very scarce in the field of NSAID. The best correlation was obtained with salicylates for which ranges of plasma concentrations needed for observing therapeutic effects in rheumatoid arthritis as well as in juvenile rheumatoid arthritis have been established. Similar correlations have been made for side effects such as tinnitus or headaches as well as for toxic manifestations of salicylism. However, many individual variations have been described and there is considerable overlap between therapeutic and toxic concentrations. According to different authors there are or there are no correlations between phenylbutazone plasma levels and either its therapeutic or its side-effects. No good correlation was found in general between indomethacin plasma levels and their therapeutic effects in rheumatic diseases but high concentrations seem to be related to a higher incidence of side-effects. However, a very good correlation was described between indomethacin plasma levels and their inhibitory effects on prostaglandin (PG) biosynthesis in vivo. A good correlation between plasma levels concentrations of certain propionic acid derivatives and their inhibitory effect on PG biosynthesis in vivo was also noted but up to now no clear correlation was described between these plasma levels and the clinical effects of these drugs. There is a direct but delayed relationship between plasma levels and synovial fluid concentrations. The peak is reached later than the plasma peak and the concentration decreases more slowly than in the circulation. In conclusion, evidence of a practical interest at the present time in rheumatology to control plasma levels of NSAID is very scarce, with perhaps the exception of salicylates in certain conditions. It is clear, however, that plasma level must in some way reflect the level of the drug at its sites of action but as long as for most of our drugs we continue to ignore both their precise sites of action and the number of these sites as well as their exact distribution, pharmacokinetics and metabolism, we shall be unable to give a valid interpretation to this level except for a very small number of compounds.