Polarised transport of monocarboxylic acid type drugs across rat jejunum in vitro: the effect of mucolysis and ATP-depletion.
The transport characteristics of monocarboxylic acid type drugs (ketoprofen, ibuprofen and gemfibrozil) across the excised jejunal segments and artificial (octanol impregnated) membrane in side-by-side diffusion cells were studied. All three model drugs permeated faster across the intestinal tissue in the mucosal-to-serosal direction than in the opposite direction. No polarised transport of tested drugs was observed when the mucosal side of the intestine was treated with mucus disrupting agent, L-cysteine 1% (w/v), which significantly increased the microclimate pH at the mucosal surface of the intestine. Similar effects on the transport characteristics of model drugs and microclimate pH were observed when metabolic inhibitor, sodium azide (10mM), was present in the incubation medium. Furthermore, the direction of proton gradient across the artificial membrane was shown to significantly influence the transport of model drugs across this membrane. The results of this study indicate that the inwardly directed proton gradient maintained by the acidic microclimate pH at the intestinal surface could be considered as a driving force for the transport of monocarboxylic acid type drugs across the intestinal epithelia and could explain rapid absorption of these drugs after oral application.
Legen
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I
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia.
Zakelj
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Kristl
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D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002264:Carboxylic Acids / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology; D015248:Gemfibrozil / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D007052:Ibuprofen / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000737:chemistry / Q000378:metabolism*; D007583:Jejunum / Q000737:chemistry / Q000378:metabolism*; D007660:Ketoprofen / Q000493:pharmacokinetics; D008297:Male; D008567:Membranes, Artificial; D051381:Rats; D017208:Rats, Wistar; D019810:Sodium Azide / Q000494:pharmacology
D002264:Carboxylic Acids; D008567:Membranes, Artificial; D000255:Adenosine Triphosphate; D007660:Ketoprofen; D019810:Sodium Azide; D003545:Cysteine; D015248:Gemfibrozil; D007052:Ibuprofen