TRANSFER OF DIFFERENT NONSTEROIDAL ANTIINFLAMMATORY DRUGS VIA THE LYMPHATIC-SYSTEM IN THE RAT

The motility of lymphatic vessels is regulated by arachidonate metabol ites and can, therefore, be altered by cyclooxygenase blockers such as nonsteroidal antiinflammatory drugs (NSAIDs), To investigate the tran sfer of different NSAIDs via the lymphatic system, pharmacokinetics in plasma and lymph after peroral administration of three model compound s (namely, racemic ibuprofen, tenoxicam, and nabumetone) were investig ated in rats, Microsurgical cannulation of the thoracic duct allowed c umulative sampling of lymph fluid up to 48 hr (N = 16). Pharmacokineti c parameters in plasma were determined in a control group (N = 12). Co ncentrations of R-ibuprofen, S-ibuprofen, tenoxicam, nabumetone, and t he metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthylac etic acid (6MNA; a metabolite of nabumetone) were monitored in lymph a nd plasma by HPLC, The observed peak concentrations in lymph of the in vestigated drugs are likely to produce different biological effects wi th regard to cyclooxygenase-1 inhibition, To quantify the appearance i n lymph fluid, a ''lymphatic clearance'' of the investigated compounds was defined by dividing the amount recovered in lymph by the correspo nding 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; ten oxicam, 32.5 +/- 31.3; nabumetone, 133.6 +/- 75.2; 6MNA, 18.3 +/- 8.5 mu l/min/kg). Overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given, The known fact that lymphatic dr ainage is regulated by arachidonate metabolites suggests that NSAIDs d iffering in their transfer via the lymphatic system could result in di fferent responses of lymphatic vessels to an inflammatory fluid load.