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Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-1525-1430
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 [en]
Permeability, intestinal absorption, regional permeability, nanoparticles, nanosuspensions, absorption-modifying excipients, AMEs
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-363908ISBN: 978-91-513-0484-7 (print)OAI: oai:DiVA.org:uu-363908DiVA, id: diva2:1257421
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
List of papers
1. Regional Intestinal Permeability of Three Model Drugs in Human
Open this publication in new window or tab >>Regional Intestinal Permeability of Three Model Drugs in Human
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2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 9, p. 3013-3021Article in journal (Refereed) Published
Abstract [en]

Currently there are only a limited number of determinations of human P-eff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The P-eff of each model drug was then calculated using a validated deconvolution method. The median P-eff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 X 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 X 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 X 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional P-eff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.

Keywords
intestinal permeability, regional intestinal drug absorption, effective permeability, pharmacokinetics
National Category
Pharmaceutical Sciences Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-307864 (URN)10.1021/acs.molpharmaceut.6b00514 (DOI)000382713700016 ()27504798 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2018-10-20Bibliographically approved
2. Regional Intestinal Permeability in Rats: A Comparison of Methods
Open this publication in new window or tab >>Regional Intestinal Permeability in Rats: A Comparison of Methods
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4252-4261Article in journal (Refereed) Published
Abstract [en]

Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (P-eff) and apparent (P-app) permeability in all three regions and at both pH levels. Metoprolol had high P-eff in all regions and at both pHs and high P-app at both pHs and in all regions except the jejunum, where P-app was low. Atenolol had low P-eff in all regions and at both pHs, but had high P-app at pH 6.5 and low P-app at pH 7.4. There were good correlations between these rat in situ P-eff (SPIP) and human in vivo P-eff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.

Keywords
intestinal permeability, Ussing chamber method, single-pass intestinal perfusion, jejunum, ileum, colon, rat
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-345176 (URN)10.1021/acs.molpharmaceut.7b00279 (DOI)000417342400014 ()28920690 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-10-20Bibliographically approved
3. In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations
Open this publication in new window or tab >>In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations
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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.

Keywords
intestinal drug absorption, aprepitant nanoformulations, nanosuspensions, fasted-state simulated intestinal fluid, aqueous boundary layer
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-345174 (URN)10.1021/acs.molpharmaceut.7b00294 (DOI)000417342400012 ()28737398 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-10-20Bibliographically approved
4. Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.
Open this publication in new window or tab >>Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 222-230, article id S0939-6411(18)30760-4Article in journal (Refereed) Published
Abstract [en]

The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-363157 (URN)10.1016/j.ejpb.2018.09.022 (DOI)30266667 (PubMedID)
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-11-28Bibliographically approved
5. Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions
Open this publication in new window or tab >>Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions
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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:nbn:se:uu:diva-363192 (URN)
Available from: 2018-10-20 Created: 2018-10-20 Last updated: 2018-10-20

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