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Reversible inhibition of efflux transporters by hydrogel microdevices.
Levy, Elizabeth S; Samy, Karen E; Lamson, Nicholas G; Whitehead, Kathryn A; Kroetz, Deanna L; Desai, Tejal A.
Afiliación
  • Levy ES; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, CA, USA.
  • Samy KE; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA; UC Berkeley - UCSF Graduate Program in Bioengineering, UCSF Mission Bay Campus, San Francisco, CA, USA.
  • Lamson NG; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Whitehead KA; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Kroetz DL; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA. Electronic address: Deanna.Kroetz@ucsf.edu.
  • Desai TA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA; UC Berkeley - UCSF Graduate Program in Bioengineering, UCSF Mission Bay Campus, San Francisco, CA, USA. Electronic address: Tejal.Desai@ucsf.edu.
Eur J Pharm Biopharm ; 145: 76-84, 2019 Dec.
Article en En | MEDLINE | ID: mdl-31639417
Oral drug delivery is a preferred administration route due to its low cost, high patient compliance and fewer adverse events compared to intravenous administration. However, many pharmaceuticals suffer from poor solubility and low oral bioavailability. One major factor that contributes to low bioavailability are efflux transporters which prevent drug absorption through intestinal epithelial cells. P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two important efflux transporters in the intestine functioning to prevent toxic materials from entering systemic circulation. However, due to its broad substrate specificity, P-gp limits the absorption of many therapeutics, including chemotherapeutics and antibacterial agents. Methods to inhibit P-gp with competitive inhibitors have not been clinically successful. Here, we show that micron scale devices (microdevices) made from a commonly used biomaterial, polyethylene glycol (PEG), inhibit P-gp through a biosimilar mucus in Caco-2 cells and that transporter function is restored when the microdevices are removed. Microdevices were shown to inhibit P-gp mediated transport of calcein AM, doxorubicin, and rhodamine 123 (R123) and BCRP mediated transport of BODIPY-FL-prazosin. When in contact with Caco-2 cells, microdevices decrease the cell surface amount of P-gp without affecting the passive transport. Moreover, there was an increase in mucosal to serosal transport of R123 with microdevices in an ex-vivo mouse model and increased absorption in vivo. This biomaterial-based approach to inhibit efflux transporters can be applied to a range of drug delivery systems and allows for a nonpharmacologic method to increase intestinal drug absorption while limiting toxic effects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transporte Biológico / Hidrogeles Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Eur J Pharm Biopharm Asunto de la revista: FARMACIA / FARMACOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transporte Biológico / Hidrogeles Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Eur J Pharm Biopharm Asunto de la revista: FARMACIA / FARMACOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos