Sw. Martin et al., PHARMACODYNAMIC COMPARISON OF REGIONAL DRUG-DELIVERY FOR NONSTEROIDALANTIINFLAMMATORY DRUGS, USING THE RAT AIR-POUCH MODEL OF INFLAMMATION, Journal of Pharmacy and Pharmacology, 47(6), 1995, pp. 458-461
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.