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Roos, C., Dahlgren, D., Sjögren, E., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2019). Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions. European journal of pharmaceutics and biopharmaceutics, 142, 387-395
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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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed) Published
Abstract [en]

Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. 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 sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396543 (URN)10.1016/j.ejpb.2019.07.012 (DOI)000488654000040 ()31306752 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dahlgren, D., Roos, C., Peters, K., Lundqvist, A., Tannergren, C., Sjögren, E., . . . Lennernäs, H. (2019). Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model. European journal of pharmaceutics and biopharmaceutics, 142, 31-37
Open this publication in new window or tab >>Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 31-37Article in journal (Refereed) Published
Abstract [en]

The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

Keywords
Intestinal perfusion, Intestinal permeability, Intestinal physiology, Intestinal fluid transport
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396541 (URN)10.1016/j.ejpb.2019.06.011 (DOI)000488654000004 ()31201856 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Seidler, U., Nylander, O., Sjöblom, M., Birnir, B. & Herzig, K.-H. (2019). Gunnar Flemström's legacy in intestinal bicarbonate secretion: A homage to Gunnar Flemström and his work in intestinal bicarbonate secretion. Acta Physiologica, 227(4), Article ID e13321.
Open this publication in new window or tab >>Gunnar Flemström's legacy in intestinal bicarbonate secretion: A homage to Gunnar Flemström and his work in intestinal bicarbonate secretion
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2019 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 227, no 4, article id e13321Article in journal, Editorial material (Other academic) Published
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-398134 (URN)10.1111/apha.13321 (DOI)000496158200005 ()31152628 (PubMedID)
Available from: 2019-12-04 Created: 2019-12-04 Last updated: 2019-12-04Bibliographically approved
Dahlgren, D., Sjöblom, M. & Lennernäs, H. (2019). Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations. European journal of pharmaceutics and biopharmaceutics, 142, 411-420
Open this publication in new window or tab >>Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations
2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 411-420Article in journal (Refereed) Published
Abstract [en]

Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosa] recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396544 (URN)10.1016/j.ejpb.2019.07.013 (DOI)000488654000043 ()31306749 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dahlgren, D., Roos, C., Lundqvist, A., Tannergren, C., Sjöblom, M., Sjögren, E. & Lennernäs, H. (2018). Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.. International Journal of Pharmaceutics, 549(1-2), 239-248, Article ID S0378-5173(18)30532-5.
Open this publication in new window or tab >>Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5Article in journal (Refereed) Published
Abstract [en]

The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.

Keywords
Absorption-modifying excipients, Biopharmaceutical classification system, In vivo predictions, Intestinal perfusion, Intestinal permeability, Intestinal physiology, Permeation enhancers
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-358464 (URN)10.1016/j.ijpharm.2018.07.057 (DOI)000443255300022 ()30055302 (PubMedID)
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-11-19Bibliographically approved
Roos, C., Dahlgren, D., Sjögren, E., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2018). Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.. European journal of pharmaceutics and biopharmaceutics, 132, 222-230, Article ID S0939-6411(18)30760-4.
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)000449127600022 ()30266667 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-01-07Bibliographically approved
Dahlgren, D., Roos, C., Johansson, P., Tannergren, C., Lundqvist, A., Langguth, P., . . . Lennernäs, H. (2018). The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.. International Journal of Pharmaceutics, 547(1-2), 158-168
Open this publication in new window or tab >>The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 547, no 1-2, p. 158-168Article in journal (Refereed) Published
Abstract [en]

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

Keywords
Absorption modifiers, Bioequivalence, Intraintestinal administration, Permeation enhancers, Pharmaceutical development
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-358463 (URN)10.1016/j.ijpharm.2018.05.029 (DOI)000439096500016 ()29758344 (PubMedID)
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-09-28Bibliographically approved
Dahlgren, D., Roos, C., Lundqvist, A., Tannergren, C., Sjöblom, M., Sjögren, E. & Lennernäs, H. (2018). Time-dependent effects on small intestinal transport by absorption-modifying excipients. European journal of pharmaceutics and biopharmaceutics, 132, 19-28
Open this publication in new window or tab >>Time-dependent effects on small intestinal transport by absorption-modifying excipients
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 19-28Article in journal (Refereed) Published
Abstract [en]

The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.

Keywords
Biopharmaceutical Classification System, absorption modifiers, bioequivalence, epithelial recovery, intestinal perfusion, intestinal permeability, permeation enhancers, pharmaceutical development
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-359823 (URN)10.1016/j.ejpb.2018.09.001 (DOI)000449127600003 ()30179738 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2019-06-26Bibliographically approved
Wan Saudi, W. S. & Sjöblom, M. (2017). Neuropeptide S reduces duodenal bicarbonate secretion and ethanol-induced increases in duodenal motility in rats. PLoS ONE, 12(4), Article ID e0175312.
Open this publication in new window or tab >>Neuropeptide S reduces duodenal bicarbonate secretion and ethanol-induced increases in duodenal motility in rats
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0175312Article in journal (Refereed) Published
Abstract [en]

Alcohol disrupts the intestinal mucosal barrier by inducing metabolic and functional changes in epithelial cells. Recently, we showed that neuropeptide S (NPS) decreases duodenal motility and increases mucosal paracellular permeability, suggesting a role of NPS in the pathogenesis of disorders and dysfunctions in the small intestine. The aim of the present study was to investigate the effects of NPS on ethanol- and HCl-induced changes of duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. The effects on duodenal bicarbonate secretion, the blood-to-lumen clearance of 51Cr-EDTA, motility and transepithelial net fluid flux were investigated.

Intravenous (i.v.) administration of NPS significantly reduced duodenal mucosal bicarbonate secretion and stimulated mucosal transepithelial fluid absorption, mechanisms dependent on nitrergic signaling. NPS dose-dependently reduced ethanol-induced increases in duodenal motility. NPS (83 pmol·kg-1·min-1, i.v.) reduced the bicarbonate and fluid secretory response to luminal ethanol, whereas a 10-fold higher dose stimulated fluid secretion but did not influence bicarbonate secretion. In NPS-treated animals, duodenal perfusion of acid (pH 3) induced greater bicarbonate secretory rates than in controls. Pre-treating animals with Nω-nitro-L-arginine methyl ester (L-NAME) inhibited the effect of NPS on bicarbonate secretion. In response to luminal acid, NPS-treated animals had significantly higher paracellular permeability compared to controls, an effect that was abolished by L-NAME.

Our findings demonstrate that NPS reduces basal and ethanol-induced increases in duodenal motility. In addition, NPS increases luminal alkalinization and mucosal permeability in response to luminal acid via mechanisms that are dependent on nitric oxide signaling. The data support a role for NPS in neurohumoral regulation of duodenal mucosal barrier function and motility.

Keywords
barrier function, motility, neuropeptide S, enteroendocrine cells, ethanol, post-prandial acid, inflammatory bowel disease
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-264426 (URN)10.1371/journal.pone.0175312 (DOI)000399371900153 ()
Note

Research funders and strategic development areas:

- Emil and Ragna Börjesson Foundation

- Uppsala University

- Ministry of Education of Malaysia

- Universiti Malaysia Sabah, Malaysia

Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2018-01-11Bibliographically approved
Dahlgren, D., Roos, C., Lundqvist, A., Tannergren, C., Langguth, P., Sjöblom, M., . . . Lennernäs, H. (2017). Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA. Molecular Pharmaceutics, 14(12), 4243-4251
Open this publication in new window or tab >>Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4243-4251Article in journal (Refereed) Published
Abstract [en]

There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to-lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations.

Keywords
absorption modifiers, bioequivalence, intestinal perfusion, permeation enhancers, pharmaceutical development
National Category
Physiology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-343167 (URN)10.1021/acs.molpharmaceut.7b00353 (DOI)000417342400013 ()28737406 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-09-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1406-9389

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