Absorpcijske bariere za monokarboksilne učinkovine v tankem črevesu : doktorska disertacija = Absorption barriers for monocarboxylic drugs in the small intestine
Legen, Igor
Many therapeutic drugs have monocarboxylic group in their structure (i.e. non-steroidal anti-inflammatory drugs (NSAIDs), hypolipidemic drugs). It is generally accepted that these drugs are absorbed ...from the gastrointestinal tract according to the pH partition theory. It is difficult to explain the extensive absorption of some monocarboxylic drugs by this mechanism because these compounds are almost completely ionized in the intestinal tract. The importance of pH gradient across the apical membrane of the enterocytes in theabsorption of monocarboxylic drugs from the gastrointestinal tract has beenrecently pointed out in the literature. Some of the suggested absorption mechanisms include the contribution of special transporters for monocarboxylicdrugs (H+žmonocarboxylate co-transporter 1, MCT1), while the others do not. The importance of these mechanisms in the absorption of monocarboxylic drugs from the intestinal tract is not yet clear, because of the lack of studies on the small intestine both in vitro and in vivo. Small intestine is covered with mucus, which might affect the absorption of drugs from the alimentary tract. Therefore, we first evaluated interactions between mucus and a monocarboxylic drug fluorescein and interactions between mucus andsome guanine derivatives, which do not have monocarboxylic group in their structures. We have found that mucus interacts relatively strong with fluorescein and acyclovir (the most polar substance in the group of tested guanine derivatives), and might therefore reduce the absorption of these two substances from the alimentary tract. We have also found that the native pig gastric mucus could be in some cases replaced by the commercially available mucin dispersions in the studies on the drug-mucus interactions. In continuation, we evaluated the importance of recently suggested mechanisms in the absorption of monocarboxylic drugs. For this purpose we studied the transport of some well-absorbed monocarboxylic drugs (ketoprofen, ibuprofen and gemfibrozil) across the isolated rat small intestinal segments mounted in the side-by-side diffusion cells. We have found that the acidic microclimate on the mucosal surface of the intestine and the intracellular energy play an important role in the transport of these model monocarboxylic drugs across thesmall intestine. We have concluded that these two factors are important in the maintenance of pH gradient across the apical membrane (pHMUCOSAL SURFACE <pHINTRACELLULAR), which acts as a driving force for the absorption of monocarboxylic drugs. Our results indicate that the contribution of MCT1 in the absorption of these drugs is probably negligible. We have also observed that some characteristics (the influence of the incubation medium pH, the influence of the Na+žH+ exchanger) of the mucosal surface microclimate of the rat jejunum incubated in the buffers containing bicarbonate ions are differentfrom those observed in the previous studies using less physiological non-bicarbonate incubation buffers. This information might be important for design of the in vitro transport studies of the substances whose absorption isdependent on the microclimate pH. Besides studies on the ketoprofen absorption mechanisms we have also evaluated the increased intestinal permeability caused by this NSAID, because the increased intestinal permeability is believed to be one of the most important factors that lead to the development of small intestinal injuries during the therapy with these drugs. We have found that ketoprofen increased the permeability of a paracellular transport marker, fluorescein, across the rat small intestine in a concentration-dependent manner, which might be useful in the development of appropriate strategies for the reduction of NSAID-related gastrointestinal injuries. Flourescein can be used as a paracellular transport marker only if D-glucose is absent from the mucosal side of the intestine. We have namely observed that D-glucose at the mucosal side triggers the active transport of fluorescein across the rat jejunum in the serosal-to-mucosal direction via an apical efflux transporter for negatively charged substances (MRP). This effectof D-glucose on the MRP activity in the small intestine could at least partially explain the delayed andžor reduced absorption of some organic acid type drugs, caused by food.
Type of material - dissertation
Publication and manufacture - Ljubljana : [Legen I.], 2003
Central Technological Library of the University of Ljubljana
52047/1443 Skladišče IN: 320030268
available - outside loan, loan period: 14 days
Faculty of Pharmacy, Lj.
Knjižnica dr 615 Legen Igor Absorpcijske IN: 0007174
available - reading room
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