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In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-1525-1430
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-5586-2906
AstraZeneca R&D, S-43150 Molndal, Sweden..
Wendelsbergs Berakningskemi AB, Kyrkvagen 7B, S-43535 Molnlycke, Sweden..
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4233-4242Article in journal (Refereed) Published
Abstract [en]

Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 mu M and 200 mu M total concentrations) in phosphate buffer, one nanosuspension (200 mu M) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 mu M) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (J(disapp)) was faster for formulations containing a total concentration of aprepitant of 200 mu M than for those containing 20 mu M, but was unaffected by the presence of vesicles. The flux into the systemic circulation (J(app)) and, subsequently, the effective diffusion constant (D-eff) were calculated using the plasma concentrations. J(app) was, like J(disapp), faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.

Place, publisher, year, edition, pages
2017. Vol. 14, no 12, p. 4233-4242
Keyword [en]
intestinal drug absorption, aprepitant nanoformulations, nanosuspensions, fasted-state simulated intestinal fluid, aqueous boundary layer
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-345174DOI: 10.1021/acs.molpharmaceut.7b00294ISI: 000417342400012PubMedID: 28737398OAI: oai:DiVA.org:uu-345174DiVA, id: diva2:1188753
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08Bibliographically approved

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Roos, CarlDahlgren, DavidSjögren, ErikLennernäs, Hans

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