Pharmacodynamic comparison of regional drug delivery for non-steroidal anti-inflammatory drugs, using the rat air-pouch model of inflammation.
The inhibition of prostaglandin E2 (PGE2) synthesis by S-(+)-ibuprofen and piroxicam have been assessed following intravenous and regional (intrapouch) drug delivery using the rat air-pouch model of inflammation. Anti-inflammatory response was defined as the decrease in the area under the exudate PGE2 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 administration and could be further improved 10-fold by regional infusion, whereas regional administration of piroxicam showed no therapeutic advantage. Examination of the concentration-response using AUC revealed that for a given response, average pouch concentrations for S-(+)-ibuprofen during the PGE2 inflammatory response (3 to 10 h) was similar, irrespective of route or mode of administration. In contrast, an advantage following systemic rather than regional administration was revealed for 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 of both pharmacodynamics and pharmacokinetics when considering the potential advantage of regional administration.
Martin
S W
SW
Department of Pharmacy, University of Manchester, UK.
Stevens
A J
AJ
Brennan
B S
BS
Rowland
M
M
Houston
J B
JB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D007052:Ibuprofen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D010894:Piroxicam / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010894:Piroxicam; D015232:Dinoprostone; D007052:Ibuprofen