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Published on: December 17, 2011
P-glycoprotein attenuating effect of human intestinal fluid
Sven Deferme1, Jan Tack, Frank Lammert
1Laboratory for Pharmacotechnology and Biopharmacy, K.U.Leuven, Herestraat 49, Gasthuisberg, 3000 Leuven, Belgium.
Insights
Human intestinal fluid (HIF) can alter P-glycoprotein (P-gp) efflux, potentially reducing overestimations in drug transport studies. Components in HIF may attenuate P-gp mediated intestinal efflux, warranting further clinical investigation.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Gastrointestinal Physiology
Background:
- P-glycoprotein (P-gp) is a key efflux transporter in the intestinal epithelium, influencing drug absorption and bioavailability.
- Standard in vitro models often use buffer solutions that may not fully replicate the physiological environment of the human gut.
Purpose of the Study:
- To investigate the impact of human intestinal fluid (HIF) on P-glycoprotein (P-gp)-mediated efflux of drugs.
- To determine if HIF affects the transport of model compounds across intestinal cell monolayers.
Main Methods:
- Human intestinal fluid (HIF) was collected from healthy volunteers.
- Caco-2 cell monolayers were used to model intestinal absorption and efflux.
- Cyclosporin A (CsA) served as a P-gp substrate to assess efflux transport in the presence of varying HIF concentrations.
Main Results:
- HIF significantly decreased the secretory transport of CsA, indicating an attenuation of P-gp efflux.
- HIF moderately increased absorptive transport of CsA without compromising cell monolayer integrity.
- A potential gender-specific effect of HIF on CsA transport was observed.
Conclusions:
- The use of simple buffer solutions may overestimate the role of P-gp efflux in vitro.
- Unidentified components within HIF can modulate P-gp mediated intestinal efflux.
- Further research is needed to elucidate the clinical relevance of HIF's P-gp modulating effects.
Purpose:
To evaluate the effect of human intestinal fluid (HIF) on P-glycoprotein (P-gp)-mediated efflux.
Methods:
HIF was obtained from eight healthy volunteers by duodenal aspiration. HIF was applied at different concentrations (0-75%) to the apical compartment of the Caco-2 system. Cyclosporin A (CsA) was used as a model compound for P-gp mediated efflux.
Results:
When the bidirectional transport of CsA across Caco-2 monolayers was assessed, a significant polarity in transport could be observed, the absorptive transport being much lower than the secretory transport. Inclusion of HIF resulted in a moderate increase of the absorptive transport, as well as a significant concentration dependent decrease of the secretory transport, without compromising the integrity of the monolayer. Interestingly, a possible gender difference could be detected as inclusion of HIF obtained from female subjects resulted in a decreased absorptive transport of CsA, whereas inclusion of HIF obtained from male subjects resulted in an increased absorptive transport. The P-gp modulating effect of HIF is not caused by a lack of glucose as an energy source for the efflux mechanism when high concentrations of HIF were present in the buffer used.
Conclusions:
The results of this study indicate that the contribution of P-gp efflux carriers may be overestimated when using salt buffer solutions as transport media. Additionally, it can be concluded that (presently unidentified) components of HIF may attenuate the P-gp mediated intestinal efflux. The clinical significance of this modulating effect remains to be investigated.
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