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ABSTRACT:The effect of discrete esters and ester mixtures on the intestinal stability and absorption of tenofovir disoproxil fumarate (tenofovir DF, an esterase-sensitive prodrug of the antiviral tenofovir) was compared with the effect of strawberry extract, which has been shown to enhance the absorption of the prodrug across Caco-2 monolayers and in rat ileum. In addition, the mechanism of absorption enhancement was investigated. In rat intestinal homogenates, complete inhibition of the conversion of tenofovir DF (as obtained by strawberry extract) could only be obtained at relatively high concentrations of the discrete esters or by using mixtures of esters (e.g., propyl p-hydroxybenzoate 0.02%, octyl acetate 0.02%, ethyl caprylate 0.01%). Coincubation of tenofovir DF with this mixture also resulted in an enhancement of its absorption in the in vitro Caco-2 system as well as in rat ileum. As tenofovir DF is a substrate for P-glycoprotein (P-gp)-related efflux carriers in the Caco-2 model, the modulatory effect of the ester mixtures was studied on the functionality of P-gp using cyclosporin A (CsA) as a model substrate. Strawberry extract as well as the mixture of three esters interfered with the absorptive transport of CsA across Caco-2 monolayers, illustrating that both mixtures interfere with both esterase-activity and P-gp functionality. This concerted barrier was not observed in rat ileum, suggesting differential functional activities of the biochemical barrier toward tenofovir DF in different absorption systems. Overall, our results illustrate that modulation of the biochemical barrier (metabolism and efflux) of tenofovir DF by ester mixtures can be used to increase the intestinal absorption of tenofovir DF in an in vitro and an in situ absorption model; the mechanism of action appears to be a complex interplay of different systems; the differential expression of carriers and enzymes in different systems illustrates the difficulty of extrapolating observations between different systems/species.

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.

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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 lowerthan the secretorytransport (polarityfactor: PF approximately 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.