PHARMACODYNAMIC COMPARISON OF REGIONAL DRUG-DELIVERY FOR NONSTEROIDALANTIINFLAMMATORY DRUGS, USING THE RAT AIR-POUCH MODEL OF INFLAMMATION

The inhibition of prostaglandin E(2) (PGE(2)) synthesis by S-(+)-ibupr ofen and piroxicam have been assessed following intravenous and region al (intrapouch) drug delivery using the rat air-pouch model of inflamm ation. Anti-inflammatory response was defined as the decrease in the a rea under the exudate PGE(2) concentration-time curve between 3 and 10 h, following regional administration of the irritant carrageenan. Dose -response studies indicated that bolus regional administration of S-()-ibuprofen increased potency 30-fold compared with systemic administr ation and could be further improved 10-fold by regional infusion, wher eas regional administration of piroxicam showed no therapeutic advanta ge. Examination of the concentration-response using AUC revealed that for a given response, average pouch concentrations for S-(+)-ibuprofen during the PGE(2) inflammatory response (3 to 10 h) was similar, irre spective of route or mode of administration. In contrast, an advantage following systemic rather than regional administration was revealed f or piroxicam, based on plasma concentration-response data, indicating a major systemic anti-inflammatory component for piroxicam but not for S-(+)-ibuprofen. These observations stress the need to take account o f both pharmacodynamics and pharmacokinetics when considering the pote ntial advantages of regional administration.