CONCENTRATION-RESPONSE RELATIONSHIPS FOR 3 NONSTEROIDAL ANTIINFLAMMATORY DRUGS IN THE RAT INTESTINE

1. The effect of diclofenac, piroxicam and (S+)-ibuprofen upon the rat intestine has been measured at constant drug plasma concentrations in the rat, using (Cr-51)-EDTA intestinal permeation as a measure of dam age. Initially disposition studies after sc administration of the thre e NSAIDs were carried out. From these studies it was found that consta nt-rate iv infusions were necessary to maintain plasma concentrations of diclofenac and (S+)-ibuprofen. Administration of piroxicam by sc bo lus gave relatively constant plasma concentrations, thus iv infusions were not necessary to obtain concentration-response data for this drug . Relative potency was found by comparing the concentration-response p rofiles of the three NSAIDs and the rank order of potency obtained was : diclofenac > piroxicam > (S+)-ibuprofen. 2. The effect of mode of ad ministration upon intestinal damage was also investigated using diclof enac. Intestinal permeability was measured in rats given diclofenac ei ther by sc bolus or iv infusion and dose-response data compared. It wa s found that for the same dose, administration by sc bolus gave a high er degree of damage than by iv infusion.