uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Regional Intestinal Permeability of Three Model Drugs in Human
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
AstraZeneca R&D, Gothenburg, Sweden..
AstraZeneca R&D, Gothenburg, Sweden..
Visa övriga samt affilieringar
2016 (Engelska)Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, nr 9, s. 3013-3021Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2016. Vol. 13, nr 9, s. 3013-3021
Nyckelord [en]
intestinal permeability, regional intestinal drug absorption, effective permeability, pharmacokinetics
Nationell ämneskategori
Farmaceutiska vetenskaper Gastroenterologi
Identifikatorer
URN: urn:nbn:se:uu:diva-307864DOI: 10.1021/acs.molpharmaceut.6b00514ISI: 000382713700016PubMedID: 27504798OAI: oai:DiVA.org:uu-307864DiVA, id: diva2:1048903
Forskningsfinansiär
EU, FP7, Sjunde ramprogrammet, FP7/2007-013Tillgänglig från: 2016-11-22 Skapad: 2016-11-22 Senast uppdaterad: 2018-10-20Bibliografiskt granskad
Ingår i avhandling
1. Biopharmaceutical aspects of intestinal drug absorption: Regional permeability and absorption-modifying excipients
Öppna denna publikation i ny flik eller fönster >>Biopharmaceutical aspects of intestinal drug absorption: Regional permeability and absorption-modifying excipients
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Before an orally administered drug reaches the systemic circulation, it has to dissolve in the intestinal fluids, permeate across the intestinal epithelial cell barrier, and pass through the liver. The permeation rate of drug compounds can be low and show regional differences.

The thesis had two general aims. The first of these was, to determine and compare regional intestinal permeability values of model compounds in human and dog. The second was to understand the possible effects of absorption-modifying pharmaceutical excipients (AMEs) on the intestinal permeability of the model compounds. The usefulness of several preclinical animal models for predicting the impact of regional intestinal permeability and AMEs in human was also investigated.

There was a good correlation between human and dog permeability values in the small intestines for the model compounds. The colon in dog was substantially more permeable than the human colon to the low permeability drug, atenolol. This difference in colonic permeability may have implications for the use of dog as a model species for prediction of human intestinal drug absorption.

There were no effects of AMEs on the intestinal permeability of any of the high permeability compounds, in any animal model. In the rat single-pass intestinal perfusion model, there was a substantial increase in permeability of all low permeability drugs, induced by two AMEs, chitosan and SDS. This AME-induced increase was substantially lower in the more in vivo relevant rat and dog intraintestinal bolus models. A shorter AME exposure-time in the rat single-pass intestinal perfusion model (15 vs. 75 min) could, however, predict the result from the bolus studies in rat and dog. This illustrates the impact of intestinal transit and mucosal exposure time on AME effects in vivo. The intestinal luminal conditions and enteric neural activity also had an impact on determinations of drug permeability in the rat single-pass intestinal perfusion model, which can have implications for its in vivo relevance.

In summary, this thesis used multiple in vivo models to evaluate the impact of several biopharmaceutical processes on intestinal drug absorption. This has led to an increased understanding of these absorption mechanisms.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 257
Nyckelord
intestinal permeability, absorption-modifying excipients
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Biofarmaci
Identifikatorer
urn:nbn:se:uu:diva-358467 (URN)978-91-513-0442-7 (ISBN)
Disputation
2018-11-02, B41, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-10-10 Skapad: 2018-09-12 Senast uppdaterad: 2018-10-16
2. Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
Öppna denna publikation i ny flik eller fönster >>Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 73
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 260
Nyckelord
Permeability, intestinal absorption, regional permeability, nanoparticles, nanosuspensions, absorption-modifying excipients, AMEs
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Biofarmaci
Identifikatorer
urn:nbn:se:uu:diva-363908 (URN)978-91-513-0484-7 (ISBN)
Disputation
2018-12-07, A1:107A, Uppsala Biomedical Centre, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-11-14 Skapad: 2018-10-20 Senast uppdaterad: 2018-11-30

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltextPubMed

Sök vidare i DiVA

Av författaren/redaktören
Dahlgren, DavidRoos, CarlHellström, Per M.Sjögren, ErikLennernäs, Hans
Av organisationen
Institutionen för farmaciGastroenterologi/hepatologi
I samma tidskrift
Molecular Pharmaceutics
Farmaceutiska vetenskaperGastroenterologi

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 474 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf