Intestinal behavior of the ester prodrug tenofovir DF in humans

International Journal of Pharmaceutics
Sophie GeboersPatrick Augustijns

Abstract

Tenofovir-disoproxil-fumarate (TDF) is a double ester prodrug which enables intestinal uptake of tenofovir (TFV) after oral administration in humans. In this study, prodrug stability was monitored in situ in the human intestine and in vitro using biorelevant media. In fasted state human intestinal fluids, the prodrug was completely degraded within 90 min, resulting in the formation of the mono-ester intermediate and TFV; in fed state intestinal fluids, the degradation rate of TDF was slightly reduced and no TFV was formed. Intestinal fluid samples aspirated after administration of TDF confirmed extensive intraluminal degradation of TDF in fasted state conditions; a relatively fast absorption of TDF partly compensated for the degradation. Although food intake reduced intestinal degradation, the systemic exposure was not proportionally increased. The lower degradation in fed state conditions may be attributed to competing esterase substrates present in food, lower chemical degradation in the slightly more acidic environment and micellar entrapment, delaying exposure to the "degrading" intestinal environment. The results of this study demonstrate premature intestinal degradation of TDF and suggest that TFV may benefit from a more ...Continue Reading

References

Sep 23, 2000·International Journal of Pharmaceutics·J Van GelderP Augustijns
Jul 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J van GelderP Augustijns
Jun 12, 2003·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Rolf W SparidansJos H Beijnen
Dec 24, 2005·Journal of Pharmaceutical Sciences·Joachim BrouwersPatrick Augustijns
May 17, 2011·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Sarah ClaryssePatrick Augustijns
Dec 14, 2011·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·A S BordeB Abrahamsson
Feb 6, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Joachim Brouwers, Patrick Augustijns

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Citations

Aug 1, 2015·Journal of Pharmaceutical Sciences·Danny RiethorstPatrick Augustijns
Apr 12, 2016·Journal of Pharmaceutical Sciences·Sophie GeboersPatrick Augustijns
Jun 25, 2016·International Journal of Pharmaceutics·Sophie GeboersPatrick Augustijns
Dec 7, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Joseph ShailenderSrividya Myneni
Dec 18, 2016·Journal of Pharmaceutical Sciences·Melynda E WatkinsPaul L Domanico
Jan 16, 2019·Antimicrobial Agents and Chemotherapy·Cindy J BednaszUNKNOWN AIDS Clinical Trials Group Study A5202 Team
May 14, 2019·The Journal of Antimicrobial Chemotherapy·Kristina M BrooksJennifer J Kiser
Aug 3, 2020·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Sarah C MannJose R Castillo-Mancilla
Nov 3, 2020·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Sarah C MannJose R Castillo-Mancilla
Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Atheer ZgairPavel Gershkovich

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