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Drug Partitioning into Natural and Artificial Membranes: Data Applicable in Predictions of Drug Absorption
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

When drug molecules are passively absorbed through the cell membrane in the small intestine, the first key step is partitioning of the drug into the membrane. Partition data can therefore be used to predict drug absorption. The partitioning of a solute can be analyzed by drug partition chromatography on immobilized model membranes, where the chromatographic retention of the solute reflects the partitioning. The aims of this thesis were to develop the model membranes used in drug partition chromatography and to study the effects of different membrane components and membrane structures on drug partitioning, in order to characterize drug–membrane interactions.

Electrostatic effects were observed on the partitioning of charged drugs into liposomes containing charged detergent, lipid or phospholipid; bilayer disks; proteoliposomes and porcine intestinal brush border membrane vesicles (BBMVs), and on the retention of an oligonucleotide on positive liposomes. Biological membranes are naturally charged, which will affect drug partitioning in the human body.

Proteoliposomes containing transmembrane proteins and cholesterol, BBMVs and bilayer disks were used as novel model membranes in drug partition chromatography. Partition data obtained on proteoliposomes and BBMVs demonstrated how cholesterol and transmembrane proteins interact with drug molecules. Such interactions will occur between drugs and natural cell membranes. In the use of immobilized BBMVs for drug partition chromatography, yet unsolved problems with the stability of the membrane were encountered. A comparison of partition data obtained on bilayer disks with data on multi- and unilamellar liposomes indicated that the structure of the membrane affect the partitioning. The most accurate partition values might be obtained on bilayer disks.

Drug partition data obtained on immobilized model membranes include both hydrophobic and electrostatic interactions. Such partition data should preferably be used when deriving algorithms or computer programs for prediction of drug absorption.

Place, publisher, year, edition, pages
Uppsala: Institutionen för naturvetenskaplig biokemi , 2005. , p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 40
Keyword [en]
Biochemistry, Bilayer disk, Cholesterol, Drug partitioning, Drugs, Electrostatic effects, Immobilized liposome chromatography, Liposome, Membrane protein, Model membrane, Oligonucleotide-liposome complex, Phospholipid, Phospholipid bilayer, Proteoliposome, Surfactant
Keyword [sv]
Biokemi
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-5752ISBN: 91-554-6224-3 (print)OAI: oai:DiVA.org:uu-5752DiVA, id: diva2:166261
Public defence
2005-05-20, B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-04-27 Created: 2005-04-27 Last updated: 2011-04-07Bibliographically approved
List of papers
1. Effects of cholesterol and model transmembrane proteins on drug partitioning into lipid bilayers as analysed by immobilized-liposome chromatography.
Open this publication in new window or tab >>Effects of cholesterol and model transmembrane proteins on drug partitioning into lipid bilayers as analysed by immobilized-liposome chromatography.
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2001 In: Journal of Pharmacy and Pharmacology, ISSN 0022-3573, Vol. 53, no 11, p. 1477-1487Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92932 (URN)
Available from: 2005-04-27 Created: 2005-04-27Bibliographically approved
2. Drug partition chromatography in immobilized porcine intestinal brush border membranes.
Open this publication in new window or tab >>Drug partition chromatography in immobilized porcine intestinal brush border membranes.
2004 In: Journal of Chromatography A, Vol. 1031, no 1-2, p. 107-112Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92933 (URN)
Available from: 2005-04-27 Created: 2005-04-27Bibliographically approved
3. Effects of ions and detergents in drug partition chromatography on liposomes
Open this publication in new window or tab >>Effects of ions and detergents in drug partition chromatography on liposomes
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2004 In: Journal of Chromatography A, Vol. 1030, no 1-2, p. 273-278Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92934 (URN)
Available from: 2005-04-27 Created: 2005-04-27Bibliographically approved
4. Interactions of drugs and an oligonucleotide with charged membranes analyzed by immobilized liposome chromatography
Open this publication in new window or tab >>Interactions of drugs and an oligonucleotide with charged membranes analyzed by immobilized liposome chromatography
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92935 (URN)
Available from: 2005-04-27 Created: 2005-04-27Bibliographically approved
5. Development and initial evaluation of PEG-stabilized disks as novel model membranes
Open this publication in new window or tab >>Development and initial evaluation of PEG-stabilized disks as novel model membranes
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2005 (English)In: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 113, no 2, p. 183-192Article in journal (Refereed) Published
Abstract [en]

We show in this study that stable dispersions dominated by flat bilayer disks may be prepared from a carefully optimized mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-5000] [PEG-DSPE(5000)]. By varying the content of the latter component, the average diameter of the disks can be changed in the interval from about 15 to 60 nm. The disks show excellent long-term stability, and their size and structure remain unaltered in the temperature range between 25 and 37 degrees C. The utility of the disks as artificial model membranes was confirmed and compared to uni- and multilamellar liposomes in a series of drug partition studies. Data obtained by isothermal titration calorimetry and drug partition chromatography (also referred to as immobilized liposome chromatography) indicate that the bilayer disks may serve as an attractive and sometimes superior alternative to liposomes in studies aiming at the investigation of drug-membrane interactions. The disks may, in addition, hold great potential for structure/function studies of membrane-bound proteins. Furthermore, we suggest that the sterically stabilized bilayer disks may prove interesting as carriers for in vivo delivery of protein/peptide, as well as conventional amphiphilic and/or hydrophobic, drugs.

Keyword
bilayer disks, drug partitioning, liposome, model membrane, PEG lipid, phospholipid, immobilized liposome chromatography
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-96189 (URN)10.1016/j.bpc.2004.09.006 (DOI)15617826 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2017-12-14Bibliographically approved

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