Absorption and Tissue Distribution of Drug-Like Compounds: Quantitative Structure-Activity Relationship Analysis ; Vaistinių junginių absorbcija ir pasiskirstymas audiniuose: kiekybinio struktūros ir aktyvumo ryšio analizė

Programmer

Sujets

• Absorption
• ADME
• Biochemistry
• Blood-brain barrier
• Distribution
• QSAR

Informations

• Publié par: vilnius_university
• Publié le: 01 janvier 2011
• Nombre de lectures: 71
• Poids de l'ouvrage: 3 Mo

Extrait

VILNIUS UNIVERSITY





Kiril Lanevskij




ABSORPTION AND TISSUE DISTRIBUTION
OF DRUG-LIKE COMPOUNDS: QUANTITATIVE
STRUCTURE-ACTIVITY RELATIONSHIP
ANALYSIS





Doctoral Dissertation
Physical Sciences, Biochemistry (04 P)





Vilnius, 2011 The dissertation work was carried out at the Department of Biochemistry and
Biophysics, Vilnius University in collaboration with VšĮ „Aukštieji algoritmai“
in 2007-2011.

Scientific supervisor:
dr. Remigijus Didžiapetris (VšĮ „Aukštieji algoritmai“, Physical sciences, Bio-
chemistry – 04 P)


VILNIAUS UNIVERSITETAS





Kiril Lanevskij




VAISTINIŲ JUNGINIŲ ABSORBCIJA IR
PASISKIRSTYMAS AUDINIUOSE: KIEKYBINIO
STRUKTŪROS IR AKTYVUMO RYŠIO ANALIZĖ





Daktaro disertacija
Fiziniai mokslai, biochemija (04 P)







Vilnius, 2011

Disertacija rengta 2007-2011 metais Vilniaus universiteto Gamtos mokslų fa-
kulteto Biochemijos ir biofizikos katedroje bendradarbiaujant su VšĮ „Aukštieji
algoritmai“.

Mokslinis vadovas:
dr. Remigijus Didžiapetris (VšĮ „Aukštieji algoritmai“, fiziniai mokslai, bio-
chemija – 04 P)


ACKNOWLEDGEMENTS
I would like to thank my scientific advisors dr. Remigijus Didžiapetris and
director of VšĮ „Aukštieji algoritmai“ dr. Pranas Japertas for providing the pos-
sibility to conduct the research and excellent supervision.
Many thanks to my colleagues Justas Dapkūnas and Liutauras Juška for
contributing to the blood-brain distribution project; dr. Laura Steponėnienė for
her work on Caco-2 data compilation; dr. Andrius Sazonovas for valuable
scientific discussions; dr. Rytis Kubilius, Dainius Šimelevičius, and Tomas
Bukėnas for developing the software that I used for my work; and all VšĮ
„Aukštieji algoritmai“ staff for contributing to the excellent atmosphere in the
office. I would also like to kindly thank dr. Alanas Petrauskas and dr. Derek P.
Reynolds – the co-authors of my papers – this work would never be published
without their insightful ideas.
I am highly grateful to prof. dr. Vida Kirvelienė and prof. dr. Dobilas Kir-
velis for reviewing my thesis and helping to improve it by expressing their cri-
tical comments and suggestions.
My special thanks go to my parents for being so supportive throughout all
these years.
I very much appreciate the financial support that I received from Lithua-
nian State Studies Foundation.
5
TABLE OF CONTENTS
ABBREVIATIONS ......................................................................................... 8
INTRODUCTION ......................................................................................... 10
SCIENTIFIC NOVELTY .............................................................................. 13
STATEMENTS FOR DEFENSE ................................................................... 14
1. LITERATURE OVERVIEW ..................................................................... 15
1.1. Plasma protein binding ........................................................................ 16
1.1.1. Proteins involved in drug binding ................................................. 17
1.1.2. Experimental determination of plasma binding ............................. 21
1.2. Partitioning into tissues. Volume of distribution .................................. 24
1.3. Blood-brain barrier .............................................................................. 29
1.3.1. Anatomy and functions ................................................................. 29
1.3.2. Quantitative blood-brain transport parameters .............................. 32
1.3.3. Experimental determination of blood-brain transport .................... 33
1.4. Gastrointestinal barrier ........................................................................ 36
1.4.1. Mucosal epithelium ...................................................................... 37
1.4.2. Experimental determination of absorption .................................... 38
1.4.3. Permeability in Caco-2 monolayers .............................................. 40
1.5. Membrane permeation mechanisms ..................................................... 41
1.6. Overview of earlier QSAR studies ....................................................... 51
1.6.1. Distribution .................................................................................. 51
1.6.2. Blood-brain transport .................................................................... 57
1.6.3. Intestinal permeability and absorption .......................................... 64
2. DATA & METHODS ................................................................................ 67
2.1. Experimental data ................................................................................ 67
2.1.1. Plasma protein binding and volume of distribution ....................... 67
2.1.2. Blood-brain transport .................................................................... 68
2.1.3. Intestinal permeability .................................................................. 71
2.2. Descriptors .......................................................................................... 74
2.2.1. Fragmental descriptors .................................................................. 74
2.2.2. Physicochemical properties........................................................... 76
6
2.3. Statistical methods ............................................................................... 77
2.3.1. GALAS modeling methodology ................................................... 77
2.3.2. Non-linear regression.................................................................... 80
2.3.3. Linear discriminant analysis ......................................................... 81
2.4. Software .............................................................................................. 82
3. THEORY ................................................................................................... 83
3.1. General considerations ........................................................................ 83
3.2. Membrane permeability ....................................................................... 84
3.3. Tissue-plasma partitioning................................................................... 89
4. RESULTS & DISCUSSION ...................................................................... 94
4.1. Plasma protein binding ........................................................................ 94
4.2. Blood-brain barrier permeability ......................................................... 97
4.3. Human intestinal absorption ................................................................ 99
4.4. Caco-2 permeability .......................................................................... 102
4.5. Blood-brain distribution .................................................................... 106
4.6. Volume of ...................................................................... 110
4.7. Generalized models of permeability and distribution ......................... 112
4.7.1. Membrane permeability .............................................................. 112
4.7.2. Tissue distribution ...................................................................... 116
4.8. CNS access........................................................................................ 121
CONCLUSIONS ......................................................................................... 129
APPENDIX ................................................................................................. 130
REFERENCES ............................................................................................ 136
LIST OF PUBLICATIONS.......................................................................... 155
SUMMARY IN LITHUANIAN (REZIUMĖ) .............................................. 156


7
ABBREVIATIONS
A – Overall solute hydrogen bonding acidity
AAG – α -Acid Glycoprotein 1
ABC – ATP Binding Cassette superfamily
ADME – Absorption, Distribution, Metabolism, Excretion
AFE – Average Fold Error
ANN – Artificial Neural Network
AUC – Area Under the Curve
B – Overall solute hydrogen bonding basicity
BBB – Blood-Brain Barrier
BUI – Brain Uptake Index
Caco-2 – human Colonic AdenoCarcinoma derived cell line
CNS – Central Nervous System
c – Steady state concentration of drug SS
c – Unbound steady-state concentration of drug u,SS
E – Excess solute molar refraction
F – Oral Bioavailability
f – Fraction unbound in brain u,br
f – in microsomal incubation u,inc
f – Fraction unbound in plasma u,pl
f – in tissue u,ti
GALAS – Global, Adjusted Locally According to Similarity modeling metho-
dology
GFA – Genetic Function Approximation
HIA – Human Intestinal Absorption
HPAC – High Performance Affinity Chromatography
HPLC – High Performance Liquid Chromatography
HSA – Human Serum Albumin
IAM – Immobilized Artificial Membrane
IV – Intravenous administration route