In Vitro, Ex Vivo, and In Situ Intestinal Absorption Characteristics of the Antiviral Ester Prodrug Adefovir Dipivoxil

Annaert, Pieter; Tukker, Josef J.; Gelder, J. Van; Naesens, Lieve; Clercq, Erik De; Mooter, Guy Van den; Kinget, Renaat; Augustijns, Patrick

doi:10.1002/1520-6017(200008)89:8<1054::aid-jps10>3.0.co;2-5

Cited by 34 publications

(16 citation statements)

References 23 publications

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“…Based on the in-house experience with the in situ perfusion approach in rats (Annaert et al, 2000;Deferme et al, 2002;van Gelder et al, 2002;Mols et al, 2005;Mellaerts et al, 2008), we successfully downscaled the technique to mice. The mean mesenteric blood flow rate (calculated based on the collected blood volumes) amounted to 46 Ϯ 13 l/min, which corresponds to the infusion rate of donor blood (50 l/min).…”

Section: Downscaling the Intestinal Perfusion Technique To Micementioning

confidence: 99%

Intestinal Perfusion With Mesenteric Blood Sampling in Wild-Type and Knockout Mice

Mols¹,

Brouwers²,

Schinkel³

et al. 2009

Drug Metab Dispos

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ABSTRACT:In the present study, we successfully downscaled, for the first time, the in situ intestinal perfusion technique with mesenteric blood sampling from rat to mouse. To evaluate the feasibility of this approach, we assessed the apparent permeability (P app ) of mouse intestine for a set of marker compounds [atenolol, paracellular transport; metoprolol, transcellular transport; talinolol, P-glycoprotein (P-gp)-mediated efflux] in both wild-type and P-gp-deficient mice. In wild-type mice, the observed P app values for atenolol (1.8 ؎ 0.3 ؋ 10 ؊6 cm/s) and metoprolol (50.2 ؎ 20.1 ؋ 10 ؊6 cm/s) were not significantly affected by inclusion of the P-gp inhibitor verapamil. In contrast, the P app value for talinolol (0.9 ؎ 0.3 ؋ 10 ؊6 cm/s) increased 5-fold in the presence of verapamil. The similarity between these values and previously determined P app values in rats indicates comparable passive barrier functions and P-gpmediated efflux transport between mice and rats. In comparison with wild-type mice, the apparent permeability in P-gp-deficient mdr1a/1b(؊/؊) mice was significantly altered for talinolol (7-fold increase) but not for atenolol or metoprolol. Because of the availability of knockout mice, the intestinal perfusion technique with mesenteric blood sampling in mice may become an important tool to elucidate the role of intestinal metabolism and active transport in drug absorption during preclinical drug evaluation.Accurate assessment of intestinal permeability for drugs and drug candidates intended for oral administration is crucial to making rational decisions according to the absorption potential and to unraveling absorption mechanisms that may explain limited and/or variable bioavailability. For instance, intestinal metabolism and active transport (uptake or efflux) might affect the rate of transepithelial drug transport and mediate drug-drug and drug-food interactions, possibly causing variable drug disposition, decreased efficiency, or unwanted side effects (Fleisher et al., 1999;Custodio et al., 2008). Among the variety of permeability models available to study transepithelial transport, the in situ intestinal perfusion technique with mesenteric blood sampling in animal models (mostly rats) is the appropriate approach when biorelevance and accurate prediction rather than high-throughput screening are required. The technique provides the best simulation of the in vivo situation (including relevant barrier functions and sink conditions. In particular, the biorelevant expression of intestinal enzymes and transporters makes the model well suited to elucidate their impact on the absorption process, even though interspecies differences may complicate extrapolation to humans.

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Section: Downscaling the Intestinal Perfusion Technique To Micementioning

confidence: 99%

Intestinal Perfusion With Mesenteric Blood Sampling in Wild-Type and Knockout Mice

Mols¹,

Brouwers²,

Schinkel³

et al. 2009

Drug Metab Dispos

Self Cite

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show abstract

“…In situ perfusion experiments were performed based on a previously described method (Annaert et al, 2000, Van Gelder et al, 2000a. Male Wistar rats (Ϯ300 g, Animalium, K. U. Leuven, Leuven, Belgium) were used.…”

Section: Chemicalsmentioning

confidence: 99%

Intestinal Absorption Enhancement of the Ester Prodrug Tenofovir Disoproxil Fumarate through Modulation of the Biochemical Barrier by Defined Ester Mixtures

Gelder

Deferme²,

Naesens³

et al. 2002

Drug Metab Dispos

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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.

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“…Also, the levels of enzymes obtained by both methods do not always reach the activity observed in vivo 35,36. The inability to study regional intestinal differences in oral absorption may be overcome by using other techniques such as intestinal tissues mounted in modified Ussing chambers37,38 or perfused intestinal segments 17. These techniques permit studying site‐dependent carrier‐mediated absorption and/or metabolism of drug compounds 39,40…”

Section: Introductionmentioning

confidence: 99%

Biological, Pharmaceutical, and Analytical Considerations with Respect to the Transport Media Used in the Absorption Screening System, Caco-2

Ingels

Augustijns

2003

Journal of Pharmaceutical Sciences

106

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In Vitro, Ex Vivo, and In Situ Intestinal Absorption Characteristics of the Antiviral Ester Prodrug Adefovir Dipivoxil

Cited by 34 publications

References 23 publications

Intestinal Perfusion With Mesenteric Blood Sampling in Wild-Type and Knockout Mice

Intestinal Perfusion With Mesenteric Blood Sampling in Wild-Type and Knockout Mice

Intestinal Absorption Enhancement of the Ester Prodrug Tenofovir Disoproxil Fumarate through Modulation of the Biochemical Barrier by Defined Ester Mixtures

Biological, Pharmaceutical, and Analytical Considerations with Respect to the Transport Media Used in the Absorption Screening System, Caco-2

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