Transfer of different nonsteroidal antiinflammatory drugs via the lymphatic system in the rat

The motility of lymphatic vessels is regulated by arachidonate metabolites and can, therefore, be altered by cyclooxygenase blockers such as nonsteroidal antiinflammatory drugs (NSAIDs). To investigate the transfer of different NSAIDs via the lymphatic system, pharmacokinetics in plasma and lymph after peroral administration of three model compounds (namely, racemic ibuprofen, tenoxicam, and nabumetone) were investigated in rats. Microsurgical cannulation of the thoracic duct allowed cumulative sampling of lymph fluid up to 48 hr (N = 16). Pharmacokinetic parameters in plasma were determined in a control group (N = 12). Concentrations of R-ibuprofen, S-ibuprofen, tenoxicam, nabumetone, and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthylacetic acid (6MNA; a metabolite of nabumetone) were monitored in lymph and plasma by HPLC. The observed peak concentrations in lymph of the investigated drugs are likely to produce different biological effects with regard to cyclooxygenase-1 inhibition. To quantify the appearance in lymph fluid, a "lymphatic clearance" of the investigated compounds was defined by dividing the amount recovered in lymph by the corresponding area under the plasma concentration-time curve. The "lymphatic clearance" differed substantially between the investigated compounds (mean +/- SD: R-ibuprofen, 19.8 +/- 9.4; S-ibuprofen, 9.6 +/- 3.6; tenoxicam, 32.5 +/- 31.3; nabumetone, 133.6 +/- 75.2; 6MNA, 18.3 +/- 8.5 microliters/min/kg). Overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given. The known fact that lymphatic drainage is regulated by arachidonate metabolites suggests that NSAIDs differing in their transfer via the lymphatic system could result in different responses of lymphatic vessels to an inflammatory fluid load.