[The tissue cage in dogs--a pharmacologic model for the representation of plasma and tissue kinetics]

Determination of pharmacokinetic data from plasma often is not sufficient in order to predict or to explain the clinical efficacy of drugs, e.g., in non steroidal antiinflammatory drugs (NSAID) with short elimination half lives in plasma a discrepancy appears between elimination half life and clinical effect. We have studied the tissue kinetics of a drug having a long elimination half life (naproxen) in comparison with phenylbutazone and flunixin, having a short elimination half life in dogs after oral application. Tissue fluid was obtained by using so called "tissue cages" implanted laterally in the neck. An inflammatory response was produced by injecting 1-2 ml of 2% carrageenan into the chamber. The drug concentrations were determined throughout the experiments both in plasma and tissue fluid. Naproxen concentrations (elimination half life of about 72 h in dogs) achieved equilibrium between tissue fluid and plasma concentration. In the case of phenylbutazone, concentration in tissue fluid declined with a definitely longer half life than in plasma and exceeded plasma concentrations after some hours. Flunixin concentrations in plasma and exudate attained equilibrium after 2-5 h. Of clinical importance is the finding that after this time flunixin accumulated in inflammatory exudate and the concentration in exudate exceeded that in plasma two to ten times, then declined with an almost identical half-life. The number of leukocytes in exudate as a measure of inflammation was reduced during 2 days after phenylbutazone, 3-4 days after flunixin and 5-7 days after naproxen. This allows therapy with a lower dosage than calculated on the basis of plasma concentrations in the case of phenylbutazone and flunixin, possibly also with other NSAIDs having a short plasma half life.