Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption

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 chromatograph...

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Bibliographic Details
Main Author: Engvall, Caroline
Format: Doctoral Thesis
Language:English
Published: Uppsala universitet, Institutionen för naturvetenskaplig biokemi 2005
Subjects:
Online Access:http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5752
http://nbn-resolving.de/urn:isbn:91-554-6224-3
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spelling ndltd-UPSALLA1-oai-DiVA.org-uu-57522013-01-08T13:07:18ZDrug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug AbsorptionengEngvall, CarolineUppsala universitet, Institutionen för naturvetenskaplig biokemiUppsala : Institutionen för naturvetenskaplig biokemi2005BiochemistryBilayer diskCholesterolDrug partitioningDrugsElectrostatic effectsImmobilized liposome chromatographyLiposomeMembrane proteinModel membraneOligonucleotide-liposome complexPhospholipidPhospholipid bilayerProteoliposomeSurfactantBiokemiBiochemistryBiokemiWhen 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. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5752urn:isbn:91-554-6224-3Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, 1651-6214 ; 40application/pdfinfo:eu-repo/semantics/openAccess
collection NDLTD
language English
format Doctoral Thesis
sources NDLTD
topic 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
Biokemi
Biochemistry
Biokemi
spellingShingle 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
Biokemi
Biochemistry
Biokemi
Engvall, Caroline
Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption
description 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.
author Engvall, Caroline
author_facet Engvall, Caroline
author_sort Engvall, Caroline
title Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption
title_short Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption
title_full Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption
title_fullStr Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption
title_full_unstemmed Drug Partitioning into Natural and Artificial Membranes : Data Applicable in Predictions of Drug Absorption
title_sort drug partitioning into natural and artificial membranes : data applicable in predictions of drug absorption
publisher Uppsala universitet, Institutionen för naturvetenskaplig biokemi
publishDate 2005
url http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5752
http://nbn-resolving.de/urn:isbn:91-554-6224-3
work_keys_str_mv AT engvallcaroline drugpartitioningintonaturalandartificialmembranesdataapplicableinpredictionsofdrugabsorption
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