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Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions
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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.ORCID iD: 0000-0002-1406-9389
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(English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441Article in journal (Refereed) Submitted
Abstract [en]

The pharmaceutical industry, prescribers, and patients have all traditionally preferred oral administration of drug products. In recent years there has been an increase in drug candidates with low solubility and/or low permeability, which may limit the use of oral administration. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed, with the aim of increasing the fraction of dose absorbed. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulphate. For the poorly permeating compounds enalaprilat and atenolol, the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen, the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol was not affected by any of the excipients. The changes in magnitude in the compounds’ absorptions were in general smaller in FeSSIF than in FaSSIF, possibly due to differences in colloidal structures present in FeSSIF that made the AMEs less available. The results in FeSSIF were similar to those from bolus-dosing in rat, which further suggests that the effect of AMEs on permeability is strongly affected by interactions between AMEs and colloidal structures in the intestinal lumen. The results suggest that, when investigating the effects of AMEs, the biorelevance of the SPIP method can be increased by the addition of intraluminal constituents to the perfusate.

National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-363192OAI: oai:DiVA.org:uu-363192DiVA, id: diva2:1257419
Available from: 2018-10-20 Created: 2018-10-20 Last updated: 2018-10-20
In thesis
1. Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
Open this publication in new window or tab >>Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For successful delivery of orally given drug products, the drug compounds must have adequate solubility and permeability in the human gastrointestinal tract. The permeability of a compound is determined by its size and lipophilicity, and is usually evaluated in various pre-clinical models, including rat models.

This thesis had three major aims: 1) investigate regional permeability in human and rat intestines and evaluate two different rat models, 2) investigate the mechanisms behind absorption in nanosuspensions, and 3) investigate the effect of food on the absorption of drug molecules in solutions and suspensions, and also food’s effect on absorption modifying excipients (AMEs).

Effective human permeability values obtained using regional intra-intestinal dosing and a deconvolution method agreed with values established by perfusion from the jejunum, demonstrating the accuracy and validity of the intra-intestinal bolus-dosing approach. Single-pass intestinal perfusion (SPIP) in rats showed better correlation with human effective permeability than the Ussing chamber, and was therefore deemed the better model for predicting drug permeability in humans.

Absorption of microsuspensions and nanosuspension was investigated using rat SPIP, which showed that microsuspensions are subject to pronounced food effects, probably by partitioning of drug into the colloidal structures formed by bile acids, lecithin, and fatty acids. Nanosuspensions were less affected by food, which was attributed to fewer available nanoparticles in the fed state due to partitioning into colloidal structures, and because nanoparticles are able to cross the aqueous boundary layer on their own, increasing the concentration of drug adjacent to the epithelial membrane.

AMEs had less effect in the fed state than the fasted state when investigated using SPIP. This difference may be caused by AMEs partitioning into luminal colloidal structures, decreasing the AMEs’ effects on the intestinal membrane. It thus seems that AMEs as well as drug compounds are subject to food-drug interactions, which may either increase or decrease the effect or absorption, something that needs to be considered during development of new drug products. 

In summary, this thesis has improved the knowledge of pre-clinical absorption models and the understanding of several biopharmaceutical mechanisms important for drug absorption.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 260
Keywords
Permeability, intestinal absorption, regional permeability, nanoparticles, nanosuspensions, absorption-modifying excipients, AMEs
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-363908 (URN)978-91-513-0484-7 (ISBN)
Public defence
2018-12-07, A1:107A, Uppsala Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-11-14 Created: 2018-10-20 Last updated: 2018-11-30

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Roos, CarlDahlgren, DavidSjögren, ErikSjöblom, MarkusHedeland, MikaelLennernäs, Hans
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