S. Deferme

The effect of food components on the absorption of P-gp substrates: a review.

P‐glycoprotein (P‐gp), a well characterized efflux mechanism which is functionally expressed in the intestinal epithelium, constitutes, along with intestinal metabolism, an important part of the biochemical barrier function of the intestinal mucosa. This efflux carrier may be responsible for limiting the bioavailability of several drugs after oral intake. Recently, increasing attention is being paid to the interaction of dietary components with the intestinal absorption of drugs. This review focuses on the modulating capacity of food components on the intestinal absorption of P‐gp substrates. The possible P‐gp inhibitory effects of several dietary constituents are discussed. In addition, this review will also focus on the effect of several bioflavonoids on the P‐gp‐mediated efflux of drugs. As the role of P‐gp (and other efflux carriers, including multidrug resistance‐associated proteins and breast cancer resistance protein) in limiting the bioavailability of drugs becomes more clear, more research is required firstly to identify the effect of dietary compounds on these efflux carriers and secondly to reveal the clinical relevance of this interaction.

Inhibitory effect of fruit extracts on P-glycoprotein-related efflux carriers: an in-vitro screening.

In this study, standardized food extracts were screened for their possible inhibitory effect on the P‐glycoprotein (P‐gp)‐mediated efflux of 3H‐ciclosporin A (CsA) using the in‐vitro Caco‐2 model. CsA is commonly used as a substrate for P‐gp‐related efflux carriers and is characterized by a polarity in transport, the absorptive transport being much lower than the secretory transport (polarity factor: PF ˜ 7). Of the 68 tested, nine extracts showed a decreased efflux of CsA (< 75% of the reference value) and were retained for further experiments on the bidirectional transport of CsA across Caco‐2 monolayers. Results of these experiments showed that strawberry, orange, apricot and mint extract exert an inhibitory effect on intestinal P‐gp‐related functionality (PF < 4.2). The effect of apricot extract was also studied on the bidirectional transport of talinolol, a specific P‐gp substrate; inclusion of 1 %, v/v, in the apical compartment of Caco‐2 monolayers resulted in a significantly reduced polarity in the transport of talinolol (PF reference = 15.5; PF in the presence of apricot extract = 2.5). This study suggests that co‐administration of fruit extracts might be a conceptually safe and useful strategy to enhance the intestinal absorption of P‐gp substrates. More research is necessary to characterize the impact of this inhibition on P‐gp‐related efflux mechanisms in other absorption models (in‐vitro and in‐vivo) and to identify the compounds that are responsible for this inhibitory effect.

P-Glycoprotein Attenuating Effect of Human Intestinal Fluid

AbstractPurpose. 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.

Sulfasalazine transport in in-vitro, ex-vivo and in-vivo absorption models : contribution of efflux carriers and their modulation by co-administration of synthetic nature-identical fruit extracts

Sulfasalazine is characterised by low oral bioavailability. In this study, its intestinal transport characteristics were studied in an in‐vitro, ex‐vivo and in‐situ system. The absorptive transport of sulfasalazine across Caco‐2 monolayers appeared to be lower than the secretory transport (Papp‐abs = 0.21 ± 0.02 times 10−6 cm s−1 and Papp‐secr = 2.97 ± 0.30 times 10−6 cm s−1, respectively). This polarity in transport of sulfasalazine was not mediated by P‐glycoprotein (P‐gp), as inclusion of verapamil (100 μm) did not have any effect on the transport polarity of sulfasalazine. However, inclusion of the multidrug resistance‐associated protein (MRP) inhibitors benzbromarone (50 μm) and sulfinpyrazone (1 mm), and the glutathione‐depleting agent chlorodinitrobenzene (100 μm), resulted in an increased absorptive transport of sulfasalazine in the Caco‐2 system (Papp‐abs = 0.64 ± 0.02, 0.51 ± 0.04 and 0.60 ± 0.03 times 10−6 cm s−1, respectively). The interference of carriers implies that, during absorption, interactions with food components may occur at the level of this carrier. Therefore, the effect of food extracts was studied in a parallel set of experiments. For two standardized nature‐identical fruit extracts (pineapple and apricot extract) a concentration‐dependent absorption‐enhancing effect could be observed in the Caco‐2 system. The functional expression of similar carriers was also demonstrated in rat ileum in the Ussing chamber system. Interaction studies with fruit extracts in the Ussing chamber system, as well as in the in‐situ intestinal perfusion study, revealed a 2‐ to 4‐fold increase in the absorptive transport of sulfasalazine. These results indicate that food components in the intestinal lumen can have a significant impact on the intestinal absorption characteristics of sulfasalazine by modulating the biochemical barrier function of the intestinal mucosa.

Intestinal absorption characteristics of the low solubility thiocarboxanilide UC-781

The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.