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Effect of P-glycoprotein and Cotreatment with Sofosbuvir on the Intestinal Permeation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate

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Abstract

Purpose

We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF.

Methods

Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed.

Results

TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV(TDF) and TFV(TAF)-equivalents. However, TDF and TAF were absorbed more efficiently than TFV and TEM. SOF did not inhibit intestinal efflux of TDF and TAF or affect intestinal accumulation of TFV(TDF) and TFV(TAF)-equivalents but did significantly increase the proportion of absorbed TDF.

Conclusions

TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV(TDF)-equivalents crossing the intestinal barrier. Our data thus suggest that reported increases in the TFV plasma concentrations in patients treated with SOF and TDF result either from a DDI between SOF and TDF that does not involve ABCB1 or from a DDI involving another drug used in combination therapy.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Gilead Sciences for providing TDF and TEM. We also thank all donors of ileal samples.

Funding

This study was supported by a research grant from Czech Science Foundation No. GACR 18-07281Y, Charles University grant Agency No. GAUK 364521, and project SVV No. 260 663. The analyses were performed on instruments purchased from the project EFSA-CDN (reg. no.: CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 50005, Hradec Kralove, Czech Republic

    Martin Huliciak, Veronika Halodova, Frantisek Staud, Ivan Vokral & Lukas Cerveny

  2. Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic

    Ivona Lhotska & Hana Kocova-Vlckova

  3. Department of Surgery, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic

    Tomas Dusek & Filip Cecka

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  9. Lukas Cerveny
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Contributions

Martin Huliciak: Writing - Original Draft, Methodology, Validation, Investigation, Data Curation, Formal analysis, Resources, Visualization, Project administration, Funding acquisition. Ivona Lhotska: Methodology, Validation, Investigation, Data Curation. Hana Kocova-Vlckova: Methodology, Validation, Resources. Veronika Halodova: Investigation. Tomas Dusek: Resources. Filip Cecka: Resources. Frantisek Staud: Funding acquisition. Ivan Vokral: Conceptualization, Methodology, Validation, Investigation, Resources, Supervision, Writing - Review & Editing, Funding acquisition. Lukas Cerveny: Conceptualization, Supervision, Project administration, Methodology, Writing-Original Draft, Writing - Review & Editing.

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Correspondence to Lukas Cerveny.

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Huliciak, M., Lhotska, I., Kocova-Vlckova, H. et al. Effect of P-glycoprotein and Cotreatment with Sofosbuvir on the Intestinal Permeation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate. Pharm Res 40, 2109–2120 (2023). https://doi.org/10.1007/s11095-023-03581-2

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