Lymph distribution of different non-steroidal anti-inflammatory drugs assessed by microsurgical cannulation of the thoracic duct in rat.
The motility of lymphatic vessels is regulated by arachidonate metabolites and, therefore, can be altered by cyclo-oxygenase blockers such as non-steroidal anti-inflammatory drugs (NSAIDs). In order to investigate the lymphotropic properties of different NSAIDs, pharmacokinetics in plasma and lymph following intragastric 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 hrs (n = 16). Pharmacokinetic parameters in plasma were determined in a control group (n = 12). Concentrations of R-, S-ibuprofen, tenoxicam, nabumetone and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthyl-acetic acid (6MNA, metabolite of nabumetone) were monitored in lymph and plasma by HPLC. To quantify the lymphotropic properties of the investigated compounds, a "lymphatic clearance" was defined by dividing the amount recovered in lymph fluid by the corresponding area under the plasma concentration-time curve (AUCP). The "lymphatic clearance" substantially differed between the investigated compounds (mean +/- SD: R-ibuprofen 6.71 +/- 3.15 microliters/min, S-ibuprofen 3.24 +/- 1.20 microliters/min, tenoxicam 8.74 +/- 8.11 microliters/min, nabumetone 46.05 +/- 26.08 microliters/min and 6MNA 6.32 +/- 2.96 microliters/min). The 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 might suggest that NSAIDs differing in their lymphotropic properties could result in different responses of lymphatic vessels to an inflammatory fluid load.
Ionac
M
M
2nd Surgical Clinic, University of Medicine and Pharmacy, Timişoara, Romania.
Oelkers
R
R
Brune
K
K
Geisslinger
G
G
Bordos
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D002074:Butanones / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D002404:Catheterization / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D007052:Ibuprofen / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D008196:Lymph / Q000378:metabolism*; D008297:Male; D008866:Microsurgery / Q000379:methods; D000077430:Nabumetone; D010894:Piroxicam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013897:Thoracic Duct / Q000601:surgery; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D010894:Piroxicam; D000077430:Nabumetone; D007052:Ibuprofen; C032801:tenoxicam