Concentration-response relationships for three nonsteroidal anti-inflammatory 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 (51Cr)-EDTA intestinal permeation as a measure of damage. Initially disposition studies after sc administration of the three NSAIDs were carried out. From these studies it was found that constant-rate iv infusions were necessary to maintain plasma concentrations of diclofenac and (S+)-ibuprofen. Administration of piroxicam by sc bolus 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 profiles of the three NSAIDs and the rank order of potency obtained was: diclofenac > piroxicam > (S+)-ibuprofen. 2. The effect of mode of administration upon intestinal damage was also investigated using diclofenac. Intestinal permeability was measured in rats given diclofenac either by sc bolus or iv infusion and dose-response data compared. It was found that for the same dose, administration by sc bolus gave a higher degree of damage than by iv infusion.