Effect of the enantiomers of flurbiprofen, ibuprofen, and ketoprofen on intestinal permeability.
Numerous studies have demonstrated that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) increases small intestinal permeability, and this has been suggested to be a prerequisite to enteropathy. It is believed that the inhibitory effect of chiral NSAIDs on the synthesis of prostaglandins and hence their efficacy and toxicity are mainly due to the S enantiomer. Using the urinary excretion of [51Cr]-EDTA, we have investigated the effects of three nonsteroidal anti-inflammatory drugs (flurbiprofen, ibuprofen, and ketoprofen) on small intestinal permeability in rats. Single doses of each NSAID were administered orally as either the racemate or the R or S enantiomer, the enantiomer dose being half that of the racemate. Each treatment caused a significant increase in intestinal permeability above that seen in untreated animals. The R enantiomers of all three NSAIDs increased small intestinal permeability significantly above base line, which was expected for (R)-ketoprofen and (R)-ibuprofen due to substantial chiral R to S inversion. The intestinal permeability for (R)-flurbiprofen, although minimal and likely due to 10% inversion, may also suggest prostaglandin-independent involvement. Furthermore, (S)-flurbiprofen, used at one-half the dose of the racemate, increased permeability to a similar magnitude as the racemate. This observation was similar to that previously reported for etodolac. A stereochemically pure enantiomer does not necessarily offer a safer alternative than its racemic form.
Davies
N M
NM
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wright
M R
MR
Russell
A S
AS
Jamali
F
F
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000737:chemistry / Q000494:pharmacology*; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D007660:Ketoprofen / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D005480:Flurbiprofen; D007660:Ketoprofen; D007052:Ibuprofen