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Koggel, Annette: Influence of Secretory Transporters on the Intestinal Permeability of
Cationic Drugs / Annette Koggel. - Taunusstein : Driesen, 2003 (Driesen Edition
Wissenschaft). - 212 S. ; 19 cm. Zugl.: Mainz, Universität, Dissertation, 2002 ISBN 3-936328-10-2
kart., Fadenheftung, zahlreiche, teilweise farbige Abbildungen, EUR 36,00
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Annette Koggel investigates the
influence of Organic Cation Transporters (OCT`s) and the multidrug resistance
transporter P-glycoprotein (P-gp) on the epithelial permeability of cationic
drugs by using cell-culture based in vitro transport- and radioligand binding
methods. On the basis of her results new insights into the intestinal
absorption and excretion of cationic drugs could be won.
The authoress: born in 1970; studied
Pharmacy at the Johannes Gutenberg-University in Mainz; qualified as a
pharmacist; PhD studies under the supervision of Prof. Dr. P. Langguth; Annette
Koggel works as a research associate in the department of biopharmacy and
pharmaceutical technology at Johannes Gutenberg-University School of Pharmacy
in Mainz.
Acknowledgments
First of all, I want to thank my
supervisor Prof. Dr. P. Langguth for giving me the opportunity to work on this
thesis at his department and for providing me with the interesting project. His
constructive advice, constant support and many productive discussions considerably
contributed to the progress and the completion of this work.
Furthermore,
I would like to thank Prof. Dr. H. Spahn-Langguth for providing me with many
interesting test-compounds and for helpful discussions throughout the
development of the radioligand binding assay, P.D. Dr. E. Closs from the
Department of Pharmacology, University of Mainz, for giving me the opportunity
to carry out the molecular biological investigations at the Department of
Pharmacology and her kind advice and Prof. Dr. F. Moll for supervising the
beginning of my work at the department.
Moreover,
I want to express my gratitude to Dr. A. Braun, who encouraged and supported me
from the beginning of my professional development. I highly appreciate her for
her honest words, when they are needed and her sensibility for the
“non-scientific” needs of the members of our group.
My
special thanks go to Dr. S. Kober. I feel sincerely indebted to her, not only
for her scientific support, effort and interest in my work at any time, but for
the excellent time we shared at the department, which was mainly due to her
cheerful and positive personality.
I want
to thank my lab colleague Daniel Wagner for the good and always harmonious
time. Sometimes it was quite curative to see the things from the point of view
of the “male” member of our group.
Moreover,
I want to thank my colleagues Monika Ofer, Cara Seidel, Isabell Schöttle,
Natalie Glube, Amal Abou El Ela and Karin Esser (the first member of our
after-lunch espresso group) for their great support and many funny hours at the
department.
In
particular I thank my friend and colleague Tanja Lenhardt for our good teamwork
and friendship for more than 13 years now and her steady support in every
sense, as well as Sandra Lutz, Marisa Sendra-Todo and Felicitas Hens for their
great help with the cell-cultures.
Especially
I want to express my gratitude to my brother Claus, whose advice and confidence
I appreciate most, and Patrick Schmidt for his encouragement and friendship
even over a distance of more than 1000 km.
I am
deeply indebted to my friend Jürgen Heusinger for his unlimited understanding
and greatest support over the last years and for his immense effort to organize
our life besides work and science. Without him and his help it would have been
much harder.
Most
of all I thank my parents, to whom this work is dedicated to; much to my regret
I can’t express my deep gratitude to my mother.
Mainz, in April 2003
Annette
Koggel
Table of
Contents
1 Introduction and aim of
the thesis.
1.1 Epithelial transport
mechanisms
1.1.1 Active and passive
transport mechanisms for transepithelial permeation .
1.1.2 Secretory transport
systems
1.1.2.1 Multidrug
resistance-associated proteins
1.1.2.2 Organic anion
transporting polypeptides
1.1.2.3 P-glycoprotein.
1.1.2.3.1 Structure of
P-glycoprotein
1.1.2.3.2 Substrates of
P-glycoprotein.
1.1.2.3.3 Expression of
P-glycoprotein in normal tissues
1.1.2.3.4 Mechanism of
P-glycoprotein action
1.1.2.3.5 Caco-2 cells as
a model to study P-glycoprotein transport activity
1.1.2.4 Organic cation
transporters
1.1.2.4.1 Structure of
organic cation transporters
1.1.2.4.2 Substrates of
organic cation transporters
1.1.2.4.3 Physiological
function of organic cation transporters
1.1.2.4.4 LLC-PK1 cells as a model to study organic cation transporter
activity
1.2 Models for the
evaluation of drug transport .
1.2.1 Cell cultures as in
vitro models
1.2.1.1 Direct
measurement of drug transport.
1.2.1.2 Indirect
measurement of transporter activity
1.2.1.2.1 Uptake inhibition
into suspended cells
1.2.1.2.2 In vitro-assays
for the investigation of P-glycoprotein .
1.2.2 Radioligand binding
studies .
1.2.2.1 Principles of
radioligand binding studies
1.2.2.2 Saturation
experiments and non-specific binding
1.2.2.3 Competition
experiments
1.3 Quaternary ammonium
compounds .
1.3.1 Permanently charged
quaternary ammonium compounds
1.3.2 Transiently charged
quaternary ammonium compounds
1.4 Aim of the thesis
2 Materials and Methods
2.1 High pressure liquid chromatography
for the analysis of quaternary ammonium compounds
2.1.1 Equipment and
Materials
2.1.1.1 Equipment .
2.1.1.2 Materials
2.1.1.2.1 Quaternary
ammonium compounds
2.1.1.2.2 HPLC materials
2.1.2 Chromatographic
conditions.
2.1.3 Sample preparation
and internal standards
2.2 HPLC method for the
determination of log P
2.2.1 Equipment and
Materials
2.2.1.1 Equipment .
2.2.1.2 Materials
2.2.2 Retention times of
references and quaternary ammonium compounds
2.2.3 Calculation of
capacity factors
2.2.4 Calculation of log
P values
2.3 Cell culture
2.3.1 Equipment and
Materials
2.3.1.1 Equipment .
2.3.1.2 Materials
2.3.2 Cell culturing
2.3.2.1 Caco-2 cells and
LLC-PK1 cells.
2.3.2.2 P-glycoprotein
overexpressing Caco-2 cells
2.4 Transport
experiments.
2.4.1 Equipment and
Materials
2.4.1.1 Equipment .
2.4.1.2 Materials
2.4.1.2.1 Model compounds
.
2.4.1.2.2 Quaternary
ammonium compounds
2.4.1.2.3 Materials for
transport experiments
2.4.2 Transport
experiments with Caco-2 cells
2.4.3 Transport experiments
with LLC-PK1 cells
2.4.4 Integrity of the
monolayer in transport studies
2.4.5 Measurement of 14C-tetraethylammonium bromide uptake in LLC-PK1 cells after transport experiments
2.4.6 Calculations
2.4.6.1 Transepithelial
electrical resistance (TEER)
2.4.6.2 Effective
permeability coefficient (Peff) .
2.5 Radioligand Binding
Assay
2.5.1 Equipment and
Materials
2.5.1.1 Equipment .
2.5.1.2 Materials
2.5.1.2.1 Cell culture
2.5.1.2.2 Materials for
the radioligand binding assay.
2.5.2 Cell preparation
for radioligand binding studies
2.5.3 General conditions
for the radioligand binding assay.
2.5.4 Composition of
incubation mixtures.
2.5.4.1 Non-specific
binding with different cell numbers .
2.5.4.2 Choice of
radioligand: Non-specific binding of ³H-verapamil HCl and ³H-talinolol to the
filtration unit
2.5.4.3 Saturation
experiment .
2.5.4.4 Saturation
experiment with ATP-System
2.5.4.5 Association
kinetics .
2.5.4.6 Competition
experiments in general.
2.5.5 Concentration
ranges for competition experiment
2.5.5.1 P-gp substrates
and inhibitors
2.5.5.2 Quaternary
ammonium compounds .
2.5.5.3 Beta-adrenoceptor
antagonists
2.5.5.4 Cosolvents and
surfactants
2.6 OCT uptake assay with
LLC-PK1 cells
2.6.1 Equipment and
Materials
2.6.1.1 Equipment .
2.6.1.2 Materials
2.6.2 Cell preparation
for the uptake assays .
2.6.3 General conditions
for the uptake assay .
2.6.4 Composition of
incubation mixtures.
2.6.4.1 Influence of pH
on 14C-TEA uptake.
2.6.4.2 Cell uptake and
non-specific binding at different cell numbers and temperatures
2.6.4.3 Kinetic studies.
2.6.4.4 Saturation
experiments
2.6.4.5 Uptake inhibition
experiments
2.6.5 Trans-stimulation
experiments
2.7 Calculation of IC50, KD and Bmax
2.8 Trypan blue exclusion
test
2.8.1 Equipment and
Materials
2.8.1.1 Equipment .
2.8.1.2 Materials
2.8.2 Viability of LLC-PK1 and Caco-2 cells in the presence of quaternary
ammonium compounds
2.8.2.1 Calculation
2.9 Scintillation
counting
2.9.1 Equipment and
Materials
2.9.1.1 Equipment .
2.9.1.2 Material
2.9.2 Sample preparation
2.9.2.1 Transport studies
2.9.2.2 Uptake assay and
radioligand binding assay
2.10 Molecular biological
investigations
2.10.1 Equipment and
Materials.
2.10.2 Isolation of total
RNA from Caco-2 and LLC-PK1 cells
2.10.3 Reverse Transcription-Polymerase
Chain Reaction (RT-PCR)
2.10.3.1 Reverse
transcription.
2.10.3.2 Polymerase chain
reaction (PCR)
2.10.4 Gel
electrophoresis .
2.10.5 Sequence analysis
3 Results
3.1 Development of a high
pressure liquid chromatography method for the analysis of quaternary ammonium
compounds
3.1.1 Modifications of
the existing HPLC method
3.2 Validation of the
HPLC-method
3.2.1 Specificity
3.2.2 Linearity .
3.2.3 Precision and
accuracy
3.2.4 Limit of
quantification (LOQ) .
3.2.5 Stability
3.2.6 In-process control
3.3 Permeation studies
across Caco-2 cells
3.3.1 Transport of model
compounds across Caco-2 cell monolayers
3.3.2 Transport of
quaternary ammonium compounds across Caco-2 cell monolayers
3.3.2.1 Absorptive and
secretory flux of quaternary ammonium compounds across Caco-2 cell monolayers
3.3.2.2 Effect of P-gp
inhibition on the transport of quaternary ammonium compounds across Caco-2 cell
monolayers .
3.3.2.2.1 Effect of
verapamil HCl on N-methyl- atropine nitrate transport across Caco-2 cell
monolayers
3.3.2.2.2 Effect of
verapamil HCl on the transport of selected quaternary ammonium compounds across
Caco-2 cell monolayers
3.4 Development and
optimization of a radioligand binding assay for the characterization of
P-glycoprotein.
3.4.1 Cell preparation
and incubation buffer
3.4.2 Choice of filter.
3.4.3 Choice of the
radioligand
3.4.3.1 ³H-Verapamil HCl.
3.4.3.2 ³H-Talinolol
3.4.3.3 Non-specific
binding to the filtration unit-³H-verapamil versus ³H-talinolol .
3.4.4 Cell number .
3.4.5 Temperature.
3.4.5.1 Incubation
temperature
3.4.5.2 Filtration and
washing temperature .
3.4.6 Influence of ATP on
binding properties of talinolol to P-gp
3.4.7 Kinetic studies
3.5 Validation of the
radioligand binding assay
3.5.1 Characterization of
the cell suspension
3.5.1.1 Determination of
KD and Bmax in saturation experiments.
3.5.1.2 Linearity of
radioligand binding
3.5.2 Reproducibility
3.5.3 Specificity.
3.5.3.1 Involvement of
organic cation transporters .
3.5.3.2 Competition
experiments with known P-gp substrates and inhibitors
3.5.4 Standard curve
preparation
3.6 Application of the
radioligand binding assay for the characterization of binding properties to
P-glycoprotein .
3.6.1 Interaction of
quaternary ammonium compounds with P-gp.
3.6.1.1 Cell toxicity of
quaternary ammonium compounds .
3.6.1.2 Competition
experiments with quaternary ammonium compounds.
3.6.1.3 Relationship
between partition coefficients (log P) and P-gp affinity of quaternary ammonium
compounds
3.6.1.3.1 Capacity factors
of quaternary ammonium compounds and references
3.6.1.3.2 Calculation of
log P values for quaternary ammonium compounds .
3.6.1.3.3 Correlation
between drug lipophilicity and P-gp affinity of quaternary ammonium compounds
3.6.1.3.4 Comparison of P-gp
affinity determined in radioligand binding studies and transport studies of
quaternary ammonium compounds across Caco-2 cell monolayers .
3.6.2 Interaction of
beta-adrenoceptor antagonists with P-gp
3.6.2.1 Competition
experiments with beta-adrenoceptor antagonists
3.6.2.2 Relationship
between drug lipophilicity (log P) and P-gp affinity of beta-adrenoceptor
antagonists
3.6.3 Interaction of
co-solvents and surfactants with P-gp .
3.6.3.1 Competition
experiments with co-solvents and surfactants
3.7 Interaction of
quaternary ammonium compounds with the organic cation transporter family .
3.7.1 Transport studies
of quaternary ammonium compounds across LLC-PK1 cell
monolayers .
3.7.1.1 Transport of the
model compound TEA across LLC-PK1 cell monolayers
3.7.1.2 Transport of
selected quaternary ammonium compounds across LLC-PK1 cell
monolayers
3.7.1.3 Effect of
quaternary ammonium compounds on the secretory transport of TEA
3.7.1.4 Uptake of TEA
into LLC-PK1 cell monolayers.
3.7.1.5 Effect of
quaternary ammonium compounds on basolateral uptake of TEA into LLC-PK1 cells.
3.7.2 Establishment of a
radioligand uptake assay for the investigation of OCT mediated uptake into
LLC-PK1 cells
3.7.2.1 Existing method
3.7.2.2 Cell preparation
and incubation buffer
3.7.2.3 Choice of
radioligand.
3.7.2.4 Influence of pH
and buffers on TEA uptake
3.7.2.5 Cell number.
3.7.2.6 Incubation
temperature
3.7.2.7 Kinetic studies
3.7.3 Validation of the
uptake assay
3.7.3.1 Characterization
of cell suspensions
3.7.3.1.1 Determination
of KD and Bmax in saturation experiments
3.7.3.1.2 Linearity of
TEA uptake
3.7.3.2 Reproducibility
3.7.4 Uptake assay with 14C-TEA and suspended LLC-PK1 cells –
Influence of quaternary ammonium compounds on 14C-TEA
uptake
3.7.5 Trans-stimulation
of 14C-TEA uptake into LLC-PK1 cells
.5
3.8 Molecular biological
investigations
3.8.1 Isolation of total
RNA from Caco-2 cells and LLC-PK1 cells
3.8.2 Reverse
Transcription-Polymerase Chain Reaction (RT-PCR).
3.8.2.1 OCT1
3.8.2.2 OCT2
3.8.2.3 OCT3
4 Discussion
4.1 Analytical methods .
4.1.1 HPLC method for
quaternary ammonium compounds .
4.1.2 Radioligand binding
assay for the characterization of P-gp
4.1.3 Radioligand uptake
assay for the characterization of OCT
4.2 Interaction of
permanently charged quaternary ammonium compounds with intestinal transporters.
4.2.1 Involvement of P-gp
4.2.2 Involvement of OCT
4.2.3 Intestinal
permeability of permanently charged quaternary ammonium compounds .
4.2.3.1 Intestinal
absorption
4.2.3.2 Intestinal excretion
4.3 Interaction of
beta-adrenoceptor antagonists with P-gp
5 Summary .
6 Zusammenfassung
7 References
8 Appendix .
8.1 Composition of
solutions and buffers
8.2 Validation of the
HPLC-method
8.2.1 Linearity
8.2.2 Precision and
accuracy
8.2.3 Stability .
8.3 Transport studies
across Caco-2 cell monolayers.
8.4 Interaction of
beta-adrenoceptor antagonists with P-gp
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