Intestinal absorption enhancement of the ester prodrug tenofovir disoproxil fumarate through modulation of the biochemical barrier by defined ester mixtures.
نویسندگان
چکیده
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.
منابع مشابه
Liquid Chromatography Metabolite Profiling of Tenofovir Disoproxil Fumarate Profilisanje Metabolita Tenofovir-dizoproksil- Fumarata Te^nom Hromatografijom
Ester prodrugs are commonly used to increase the intestinal absorption of drugs with permeabilitylimited absorption. The high functional activity of este rases in blood and liver allows a rapid bio acti va tion of the prodrug after reaching the sys temic circu lation. However, the increased efficiency of prodrugs to pass the intestinal barrier may be decreased by its rapid esterase-mediated hyd...
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ورودعنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 30 8 شماره
صفحات -
تاریخ انتشار 2002