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We have identified differences in transport properties of intestinal epithelia in the marsupial brushtail possum, compared to eutherian mammals. To determine whether differences in its permeability to hydrophilic compounds also occur, the absorption of sodium fluorescein and luteinizing hormone releasing hormone (LHRH) was assessed in vitro and the ability of chemical enhancers and a metabolic inhibitor to promote their absorption investigated. The apparent permeability of colonic and caecal tissues to fluorescein and LHRH and transepithelial resistance (Rt) in the absence or presence of ethylenediamine tetra-acetic acid (EDTA), sodium deoxycholic acid (SDA), dithiothreitol (DTT), polyacrylic acids (PAA), or the inhibitor bacitracin were determined. The effects of SDA and/or DTT on adherent mucus and the release of lactate dehydrogenase (LDH) were also assessed. In the absence of treatment, both tissues had comparable amounts of adherent mucus, Rt and low permeabilities to fluorescein and LHRH. All chemical enhancers increased fluorescein permeability, but SDA at concentrations >0.5 mM also induced LDH release. DTT alone and in combination with SDA reduced the amount of adherent mucus. Bacitracin inhibited LHRH metabolism and increased LHRH permeability. These data indicate that the possum hindgut epithelium represents a significant barrier to the uptake of hydrophilic compounds, similar to that in eutherians., ((c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.)

The peptidolytic activity of fresh and frozen mucosal homogenates from five regions (duodenum, jejunum, ileum, caecum and colon) of possum intestine from Trichosurus vulpecula towards human Luteinizing Hormone Releasing Hormone (LHRH) was investigated. The rank of order of specific peptidolytic activity of the mucosal homogenates was jejunum > ileum > caecum> duodenum = colon, with a 3 to 4 fold difference between the least and the most active segment in both frozen and fresh samples. The formation of peptides LHRH (1-3), LHRH (1-4) and LHRH (1-5) suggest endopepetidase-24.18, endopeptidase-24.15 and angiotensin converting enzyme (ACE) might be responsible for the peptide degradation in mucosal homogenates. The inhibition of LHRH degradation by mucosal homogenates was evaluated in four regions (jejunum, ileum, caecum and colon) of possum intestine. Ethylenediaminetetraacetic acid (EDTA, 5 mM), sodium deoxycholate (SDA, 10 mM) and bacitracin (3.5 or 9 mM) inhibited the degradation of LHRH in mucosal homogenates from small intestine and hindgut. However, the serine protease inhibitor, soybean trypsin-chymotrypsin inhibitor (SBTI), did not prevent degradation of LHRH. It is concluded that combining peptides with inhibitors may enhance oral delivery of bioactive peptides or proteins to possums.

Gastric ulceration associated with the use of NSAIDs is most frequently observed in elderly women, the same sector of society most likely to be receiving therapy for osteoporosis. As some anti-osteoporosis medications have been suggested to irritate the upper gastrointestinal mucosa, we evaluated the ability of one such drug, alendronate, to damage the gastric mucosa and to influence the severity and healing of gastric ulcers in rodents. The effects of alendronate on indomethacin-induced antral ulceration was evaluated in the rabbit, while effects on ulcer healing and on the formation of gastric erosions was evaluated in the rat. Effects of alendronate on gastric acid secretion, blood flow and prostaglandin synthesis were also evaluated. Alendronate caused erosions in the rabbit stomach, but not antral ulceration. However, at the highest doses tested (80 mg) alendronate increased the incidence and size of indomethacin-induced antral ulcers. Alendronate also enhanced indomethacin-induced gastric damage in the rat, and delayed gastric ulcer healing. These effects of alendronate were not attributable to changes in gastric acid secretion, blood flow, prostaglandin synthesis or the pharmacokinetics of indomethacin. The damaging effects of alendronate on the stomach were due to topical irritant effects and could be observed at concentrations as low as 4 mg/ml within 30 min of oral administration or topical superfusion. These results support preliminary clinical evidence that alendronate can damage the gastric mucosa. While gastric injury may be a rare occurrence in patients taking this drug, concomitant use of alendronate and NSAIDs may increase the incidence or severity of ulceration.

Numerous studies in humans have demonstrated increases in intestinal permeability resulting from the administration of non-steroidal anti-inflammatory drugs (NSAIDs). The increased permeability correlates well with ulceration. The time course of the changes in intestinal permeability, however, has not been studied, which makes comparative studies between different NSAIDs or different formulations of the same drug difficult. In the present study we have administered single doses of indomethacin to examine both the time course and pharmacokinetic/pharmacodynamic relationships of intestinal permeability in rats estimated by following the urinary excretion of [51Cr]-EDTA. The change in intestinal permeability was both time- and dose-dependent. Following both 10 mg kg-1 and 20 mg kg-1 oral doses of indomethacin, there was a rapid rise in intestinal permeability to a maximum level, after at least 12 h post-dose, which is longer than those previously observed for ibuprofen, ketoprofen, flurbiprofen and naproxen. The maximal effect lasted 12 and 36 h following 10 and 20 mg kg-1 doses, respectively. The side-effect-plasma concentration relationship demonstrated a counter-clockwise hysteresis. The relationship between the observed side-effect and the estimated deep effect compartment concentration was, on the other hand, linear. In comparative permeability studies of NSAIDs the time of administration, concentration and drug dependencies should be considered.

Although the analysis of the enantiomers of chiral non-steroidal anti-inflammatory drugs (NSAIDs) has been carried out for over 20 years, there often remains a deficit within the pharmaceutical and medical sciences to address this issue. Hence, despite world-wide therapeutic use of chiral NSAIDs the importance of stereoselectivity in pharmacokinetic, pharmacodynamic and pharmacological activity and disposition has often been ignored. This review presents both the general principles that allow separation of chiral NSAID enantiomers, and discusses both the advantages and disadvantages of the available chromatographic assay methods and procedures used to separately quantify NSAID enantiomers in biological matrices.

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.