Drug bioavailability: estimation of solubility, permeability, absorption and bioavailability
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| Format: | Book |
|---|---|
| Language: | English |
| Published: |
Weinheim
Wiley-VCH
2009
|
| Edition: | 2., completely rev. ed. |
| Series: | Methods and principles in medicinal chemistry
40 |
| Subjects: | |
| Online Access: | Inhaltstext Inhaltsverzeichnis Inhaltsverzeichnis Klappentext |
| Item Description: | Literaturangaben |
| Physical Description: | XXV, 624 S. Ill., graph. Darst. |
| ISBN: | 9783527320516 |
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| 245 | 1 | 0 | |a Drug bioavailability |b estimation of solubility, permeability, absorption and bioavailability |c ed. by Han van de Waterbeemd ... |
| 250 | |a 2., completely rev. ed. | ||
| 264 | 1 | |a Weinheim |b Wiley-VCH |c 2009 | |
| 300 | |a XXV, 624 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 490 | 1 | |a Methods and principles in medicinal chemistry |v 40 | |
| 500 | |a Literaturangaben | ||
| 650 | 4 | |a Biological Availability | |
| 650 | 4 | |a Drugs |x Bioavailability | |
| 650 | 4 | |a Pharmaceutical Preparations |x administration & dosage | |
| 650 | 4 | |a Pharmaceutical Preparations |x metabolism | |
| 650 | 4 | |a Pharmacokinetics | |
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Contents
List of Contributors
XÍX
Preface
XXIII
A Personal Foreword
XXV
1
Introduction: The Why and How of Drug Bioavailability Research
1
Han van
de Waterbeemd
and Bernard Testa
1.1
Defining Bioavailability
1
1.1.1
The Biological Context
1
1.1.2
A Pharmacokmetic Overview
3
1.1.3
Specific Issues
3
1.2
Presentation and Layout of the Book
4
References
6
Part One Physicochemical Aspects of Drug Dissolution and Solubility
7
2
Aqueous Solubility in Drug Discovery Chemistry, DMPK, and
Biological Assays
9
Nicola Coldough, Linette Ruston, and Kin
Tam
2.1
Introduction
10
2.1.1
Definition of Aqueous Solubility
11
2.1.2
Aqueous Solubility in Different Phases of Drug Discovery
12
2.2
Aqueous Solubility in Hit Identification
12
2.2.1
Aqueous Solubility from DMSO Solutions
13
2.2.1.1
Turbidimetric Methods
14
2.2.1.2
UV Absorption Methods
15
2.2.1.3
Alternative Detection Methodology
17
2.2.1.4
Application of DMSO-Based Solubffity Assays
18
Drug Bioavailabilitp Estimation of Solubility, Permeability, Absorption and
ШоаяайлЫЩ
Edited by Han
тал
de
Waterbeemd and Bernard Testa
Copyright
© 2009
WILE1-VCH "Veriag GmbH
&
Co. KGaA, Weinheim
ISBN:
978-3-527-32051-6
VI
Contents
2
3
2
3.1
2
3.2
2.3.3
2
3.4
2
3.5
2
4
Aqueous Solubility in Lead Identification and Lead
Optimization
18
Dried-Down Solution Methods
20
Solubility from Solid
21
Thermodynamic Solubility Assays with Solid-State
Characterization
22
Solubility by Potentiometry
24
Application of Thermodynamic Solubility Data in LI and
LO
26
Conclusions
28
References
28
3
Gastrointestinal Dissolution and Absorption of Class II Drugs
33
Arik
S.
Dahan and Cordon
L
Amidon
3.1
Introduction
33
3.2
Drag Absorption and the BCS
34
3.3
Class II Drags
36
3.4
GI Physiological Variables Affecting Class II Drug
Dissolution
38
3.4.1
Bile
Salts
38
3.4.2
GI
pH
39
3.4.3
GI Transit
39
ЗАЛ
Drag Parade Size
40
3.4.5
Volume Available for Dissolution
41
3.5
In Vitro Dissolution Tests for Class II Drags
41
3.5.1
Biorelevant
Media
41
3.5.2
Dynamic Lipolysis Model
42
3.6
BCS-Based FDA Guidelines: Implications for Class II Drugs
43
3.6.1
Potential of Redefining BCS Solubility Class Boundary
43
3.6.2
Biowaiver Extension Potential for Class II Drugs
44
3.7
Conclusions
45
References
45
4
In Silico Prediction of Solubility
53
Andrew M. Davis and Pierre Bruneau
4.1
Introduction
54
4.2
What Solubility Measures to Model?
54
4.3
Is the Data Set Suitable for Modeling?
56
4.4
Descriptors and Modeling Methods for Developing
Solubility Models
58
4.5
Comparing Literature Solubility Models
59
4.6
What Is the Influence of the Domain of Applicability?
63
4.7
Can We Tell when Good Predictions Are Made?
65
4.8
Conclusions
65
References
66
Contents
VII
Part Two Physicochemical and Biological Studies of Membrane Permeability
and Oral Absorption
69
5
Physicochemical Approaches to Drug Absorption
71
Han van
de Waterbeemd
5.1
Introduction
73
5.2
Physicochemical Properties and Pharmacokinetics
74
5.2.1
DMPK
74
5.2.2
Lipophilidty, Permeability, and Absorption
74
5.2.3
Estimation of Volume of Distribution from Physical Chemistry
76
5.2.4
Plasma Protein Binding and Physicochemical Properties
76
5.3
Dissolution and Solubility
76
5.3.1
Calculated Solubility
78
5.4
Ionization (piy
78
5.4.1
Calculated pKa
79
5.5
Molecular Size and Shape
79
5.5.1
Calculated Size Descriptors
79
5.6
Hydrogen Bonding
80
5.6.1
Calculated Hydrogen-Bonding Descriptors
80
5.7
lipophilicity
81
5.7.1
log
Ρ
and log
D
82
5.7.2
Calculated log
Ρ
and log
D
83
5.8
Permeability
84
5.8.1
Artificial Membranes and
PAMPA
84
5.8.1.1
In Silico
PAMPA
85
5.8.2
IAM,
ILC, MEKC, and BMC
85
5.8.3
Liposome
Partitioning
86
5.8.4
Biosensors
86
5.9
Amphiphilidty
86
5.10
Drag-Like Properties
87
5.11
Computation Versus Measurement of Physicochemical Properties
5.11.1
QSAR Modeling
88
5.11.2
In Combo: Using the Best of Two Worlds
89
5.12
Outlook
89
References
89
6
High-Throughput Measurement of Physicochemical Properties
101
Barbara P. Mason
6.1
Introduction
102
6.2
Positioning of Physicochemical Screening in Drug Discovery
102
6.3
"Fit for Purpose" Versus "Gold Standard"
103
6.4
Solubility
104
6.4.1
"Thermodynamic" Versus "Kinetic"
104
6.4.2
Methods of Measuring High-Throughput Solubility
106
VIII Contents
6.4.3
Supernatant Concentration
106
6.4.4
Measuring Solubility Across
a pH
Range
107
6.4.5
Supernatant Concentration Methods from Solid Material
109
6.4.6
Precipitate Detection
109
6.4.7
Other Methods of Measuring Solubility
110
6.5
Dissociation Constants, pK,
110
6.5.1
Measuring piCa 111
6.5.2
pKa Measurements in Cosolvent Mixtures
112
6.5.3
ρ
Ka
Measurements based on Separation
113
6.6
Lipophilicity
115
6.6.1
log
Ρ
Versus log -DpH
115
6.6.2
Measuring lipophilicity
116
6.6.3
High-Throughput log D74 Measurements
ÎJ7
6.6.4
High-Throughput log D7A Versus Shake-Flask log D7A
117
6.6.5
Alternative Methods for Determining High-Throughput
logDpH
118
6.7
Permeability
119
6.7.1
Permeability and Lipophilicity
121
6.7.2
Cell-Based Assays
121
6.7.3
Noncell-Based Assays:
Chromatographie
Methods
122
6.7.4
Noncell-Based Assays: Parallel Artificial Membrane
Permeability Assay
122
6.7.4.1
Membrane Composition
123
6.7.4.2
Suggestions for
PAMPA
123
6.7.4.3
Considerations in the Calculation of Permeability
from
PAMPA Data
124
6.7.5
Sink Conditions
125
6.7.6
Unstirred Water Layer
126
6.7.7
Surface Properties for the Determination of Permeability
126
6.8
Data Interpretation, Presentation, and Storage
126
6.9
Conclusions
127
References
127
7
An Overview of Caco-2 and Alternatives for Prediction of Intestinal
Drug Transport and Absorption
133
Anna-Lena Ungell and Per
Artursson
7.1
Introduction
134
7.2
СеД
Cultures for Assessment of Intestinal Permeability
134
7.2.1
Caco-2
135
7.2.2
MDCK Cells
136
7.2.3
2/4/A1 Cells
137
7.2.4
Other Cell lines
139
7.3
Correlation to Fraction of Oral Dose Absorbed
140
7.4
Cell Culture and Transport Experiments
141
7
A.I Quality Control and Standardization
143
Contents
IX
7.4.2
Optimizing Experimental Conditions:
pH 144
7.4.3
Optimizing Experimental Conditions: Concentration Dependence
144
7.4.4
Optimizing Experimental Conditions: Solubility and BSA
245
7.5
Active Transport Studies in Caco-2 Cels
145
7.6
Metabolism Studies using Caco-2 Cells
146
7.7
Conclusions
147
References
148
8
Use of Animals for the Determination of Absorption and
Bioavailability
161
Chris Logan
8.1
Introduction
162
8.1.1
ADME/PK in Drug Discovery
162
8.1.2
The Need for Prediction
163
8.2
Consideration of Absorption and Bioavailability
163
8.3
Choice of Animal Species
167
8.4
Methods
168
8.4.1 Radiolabels 269
8.4.2
Ex Vivo Methods for Absorption
269
8.4.2.1
Static Method
169
8.4.2.2
Perfusion
Methods
170
8.4.3
In Vivo Methods
170
8.5
In Vivo Methods for Determining Bioavailability
171
8.5.1
Cassette Dosing
171
8.5.2
Semisimultaneous Dosing
172
8.5.3
Hepatic Portal Vein Cannulation
273
8.6
Inhalation
273
8.7
Relevance of Animal Models
174
8.7.1
Models for Prediction of Absorption
274
8.7.2
Models for Prediction of Volume
275
8.8
Prediction of Dose in Man
276
8.8.1
Allometry
176
8.8.2
Physiologically Based Pharmacokinetics
2 76
8.8.3
Prediction of Human Dose
277
8.9
Conclusions
279
References
279
9
¡n Vivo Permeability Studies in the Gastrointestinal Tract
of Humans
285
Nielas
Petri
and Hans
Lennernãs
9.1
Introduction
285
9.2
Definitions of Intestinal Absorption, Presystemic Metabolism,
and Absolute Bioavailability
288
9.3
Methodological Aspects of In Vitro Intestinal
Perfusion
Techniques
190
Contents
9.4 Paracellular Passive Diffusion 193
9.5
Transcellular
Passive Diffusion 196
9.6
Carrier-Mediated
Intestinal
Absorption 199
9.7 Jejunal Transport
and Metabolism
202
9.8 Regional
Differences in
Transport
and Metabolism of Drugs
9.9
Conclusions
209
References
210
208
Part Three Role of Transporters and Metabolism in Oral Absorption
221
10
Transporters in the Gastrointestinal Tract
223
Pascale
Anderle and
Carsten
U.
Nielsen
10.1
Introduction
223
10.2
Active Transport Along the Intestine and Influence on Drug
Absorption
228
10.2.1
Peptide
Transporters
232
10.2.2
Nucleoside Transporters
233
10.2.3
Amino
Acid Transporters
234
10.2.4
Monosaccharide Transporters
234
10.2.5
Organic Cation Transporters
235
10.2.6
Organic
Anion
Transporters
235
10.2.7
Monocarboxylate Transporters
235
10.2.8
ABC Transporters
235
10.2.9
Bile Acid Transporters
237
10.3
Transporters and Genomics
237
10.3.1
Introduction to Genomics Technologies
237
10.3.2
Gene Expression Profiling Along the Intestine and in
Caco-2 Cells
238
10.3.2.1
Profiling of the Intestinal
Mucosa
238
10.3.2.2
Profiling of Caco-2 Cells
240
10.3.3
Intestinal Transporters and the Influence of Genotypes
242
10.4
Structural Requirements for Targeting Absorptive Intestinal
Transporters
245
10.4.1
Strategies for Increasing Drug Absorption
Targeting Transporters
245
10.4.2
Changing the Substrate:
SAR
Established for PEPT1
247
10.4.3
Methods for Investigating Affinity and
Translocation
248
10.4.4
Quantitative Structure-Activity Relations for Binding of
Drug to Transporters
249
10.5
Transporters and Diseased States of the Intestine
251
10.5.1
Intestinal Diseases
251
10.5.2
Basic Mechanisms in Cancer and Specifically in Colon
Carcinogenesis
252
10.5.2.1
Basic Mechanisms
252
Contents
XI
10.5.2.2
Colon Cancer
253
10.5.3
Transporters and Colon Cancer
253
10.5.3.1
Transporters as Tumor Suppressor Genes
255
10.5.3.2
Role of Transporters in the Tumor-Stroma Interaction
255
10.5.3.3
Role of Transporters in Intestinal Stem Cells
258
10.5.4
Role of PEPT1 in Inflammatory Bowel Disease
259
10.6
Summary and Outlook
260
References
261
Π
Hepatic Transport
277
Kazuya Maeda, Hiroshi Suzuki, and Yuichi Sugiyama
11.1
Introduction
278
11.2
Hepatic Uptake
278
11.2.1
NTCP (SLClOAl)
279
11.2.2
OATP
(SICO)
Family Transporters
279
11.2.3
OAT (SIC22) Family Transporters
281
11.2.4
OCT (SLC22)
Family Transporters
284
11.3
Biliary Excretion
284
11.3.1
MDR1 (P-glycoprotein; ABCBl)
287
11.3.2
MRP2 (ABCCl)
287
11.3.3
BCRP (ABCG2)
289
11.3.4
BSEP (ABCBll)
290
11.3.5
MATEI (SLC47A1)
290
11.4
Sinusoidal Efflux
290
11.4.1
MRP3 (ABCC3)
291
11.4.2
MRP4 (ABCC4)
291
11.4.3
Other Transporters
293
11.5
Prediction of Hepatobiliary Transport of Substrates from
In Vitro Data
294
11.5.1
Prediction of Hepatic Uptake Process from In Vitro Data
294
11.5.2
Prediction of the Contribution of Each Transporter to the Overall
Hepatic Uptake
295
11.5.3
Prediction of Hepatic Efflux Process from In Vitro Data
298
11.5.4
Utilization of Double (Multiple) Transfected Cells for the
Characterization of Hepatobiliary Transport
299
11.6
Genetic Polymorphism of Transporters and Its Clinical
Relevance
301
11.7
Transporter-Mediated Drug-Drug Interactions
305
11.7.1
Effect of Drugs on the Activity of Uptake Transporters Located
on the Sinusoidal Membrane
305
11.7.2
Effect of Drugs on the Activity of Efflux Transporters Located on the
Bile Canalicular Membrane
308
11.7.3
Prediction of Drug-Drug Interaction from In Vitro Data
309
11.8
Concluding Remarks
309
References
311
XII Contents
12
The Importance of Cut Wall Metabolism in Determining
Drug Bioavailability
333
Christopher Kohl
12.1
Introduction
334
12.2
Physiology of the Intestinal
Mucosa
334
12.3
Drug-Metabolizing Enzymes in the Human
Mucosa
336
12.3.1
Cytochrome P450
336
12.3.2
Glucuronyltransferase
337
12.3.3
Sulfotransferase
337
12.3.4
Other Enzymes
337
12.4
Oral Bioavailability
341
12.4.1
In Vivo Approaches to Differentiate Between Intestinal and Hepatic
First-Pass Metabolism
342
12.4.2
In Vitro Approaches to Estimate Intestinal Metabolism
344
12.4.3
Computational Approaches to Estimate and to Predict Human
Intestinal Metabolism
345
12.5
Clinical Relevance of Gut Wall First-Pass Metabolism
347
References
347
13
Modified Cell Lines
359
Cuangqing Xiao and Charles
L
Crespi
13.1
Introduction
359
13.2
Cell/Vector Systems
360
13.3
Expression of Individual Metabolic Enzymes
363
13.4
Expression of Transporters
365
13.4.1
Efflux Transporters
365
13.4.2
Uptake Transporters
367
13.5
Summary and Future Perspectives
368
References
368
Part Four Computational Approaches to Drug Absorption and Bioavailability
373
14
Calculated Molecular Properties and Multivariate Statistical Analysis
375
Ulf
Nori'nder
14.1
Introduction
377
14.2
Calculated Molecular Descriptors
377
14.2.1 2D-Based
Molecular Descriptors
377
14.2.1.1
Constitutional Descriptors
378
14.2.1.2
Fragment- and Functional Group-Based Descriptors
378
14.2.1.3
Topological Descriptors
379
14.2.2 3D
Descriptors
381
14.2.2.1
WHIM Descriptors
381
14.2.2.2
Jurs Descriptors
382
14.2.2.3
VolSurf and Almond Descriptors
383
Contents XIII
14.2.2.4 Pharmacophore
Fingerprints
384
14.2.3
Property-Based Descriptors
385
14.2.3.1
log
Ρ
385
14.2.3.2
HYBOT Descriptors
386
14.2.3.3
Abraham Descriptors
386
14.2.3.4
Polar Surface Area
386
14.3
Statistical Methods
387
14.3.1
Linear and Nonlinear Methods
388
14.3.1.1
Multiple Linear Regression
388
14.3.1.2
Partial Least Squares
389
14.3.1.3
Artificial Neural Networks
390
14.3.1.4
Bayesian Neural Networks
390
14.3.1.5
Support Vector Machines
390
14.3.1.6
fe-Nearest Neighbor Modeling
392
14.3.1.7
Linear Discriminant Analysis
3 92
14.3.2
Partitioning Methods
393
14.3.2.1
Traditional Rule-Based Methods
393
14.3.2.2
Rule-Based Methods Using Genetic Programming
394
14.3.3
Consensus and Ensemble Methods
395
14.4
Applicability Domain
396
14.5
Training and Test Set Selection and Model Validation
398
14.5.1
Training and Test Set Selection
398
14.5.2
Model Validation
399
14.6
Future Outlook
400
References
401
15
Computational Absorption Prediction
409
Christel
A.S.
Bergström, Markus Haeberlein,
and UlfNorinder
15.1
Introduction
410
15.2
Descriptors Influencing Absorption
410
15.2.1
Solubility
423
15.2.2
Membrane Permeability
412
15.3
Computational Models of Oral Absorption
413
15.3.1
Quantitative Predictions of Oral Absorption
413
15.3.1.1
Responses: Evaluations of Measurement of Fraction Absorbed
417
15.3.1.2
Model Development: Data sets, Descriptors, Technologies,
and
Applicability
419
15.3.2
Qualitative Predictions of Oral Absorption
420
15.3.2.1
Model Development: Data sets, Descriptors, Technologies,
and Applicability
420
15.3.2.2
An Example Using Genetic Programming-Based Rule Extraction
426
15.3.3
Repeated Use of Data Sets
427
15.4
Software for Absorption Prediction
427
15.5
Future Outlook
428
References
429
XIV Contents
16 In Silico
Prediction of
Human Bioavailability 433
David
J.
Livingstone
and
Han van
de Waterbeemd
16.1
Introduction
434
16.2
Concepts of Pharmacokinetics and Role of Oral
Bioavailability
437
16.3
In Silica QSAR Models of Oral Bioavailability
438
16.3.1
Prediction of Human Bioavailability
438
16.3.2
Prediction of Animal Bioavailability
442
16.4
Prediction of the Components of Bioavailability
442
16.5
Using Physiological Modeling to Predict Oral Bioavailability
443
16.6
Conclusions
445
References
446
17
Simulations of Absorption, Metabolism, and Bioavailability
453
Michael B.
Böiger,
Robert Fraczkiewicz, and
Viera
Lukacova
17.1
Introduction
454
17.2
Background
454
17.3
Use of Rule-Based Computational Alerts in Early Discovery
456
17.3.1
Simple Rules for Drug Absorption (Draggability)
456
17.3.2
Complex Rules That Include
Toxicity
473
17.4
Mechanistic Simulation (ACAT Models) in Early Discovery
474
17.4.1
Automatic Scaling
offeras
a Function of Peff,
pH,
log D, and GI
Surface Area
477
17.4.2
Mechanistic Corrections for Active Transport and Efflux
478
17 A3
PBPK and In Silico Estimation of Distribution
481
17.5
Mechanistic Simulation of Bioavailability
(Drug Development) 4S2
17.5.1
Approaches to In Silico Estimation of Metabolism
484
17.6
Regulatory Aspects of Modeling and Simulation (FDA Critical
Path Initiative)
484
17.7
Conclusions
485
References
485
18
Toward Understanding P-Clycoprotein Structure-Activity
Relationships
497
Anna Seelig
18.1
Introduction
498
18.1.1
Similarity Between P-gp and Other ABC Transporters
498
18.1.2
Why P-gp Is Special
500
18.2
Measurement of P-gp Function
500
18.2.1
P-gp ATPase Activity Assay
500
18.2.1.1
Quantification of Substrate-Transporter Interactions
503
18.2.1.2
Relationship between Substrate-Transporter Affinity and Rate
of Transport
504
18.2.2
Transport Assays
506
Contents
XV
18.2.3
Competition Assays
508
18.3
Predictive In Silico Models
508
18.3.1
Introduction to Structure-Activity Relationship
509
18.3.2
3D-QSAR Pharmacophore Models
509
18.3.3
Linear Discriminant Models
510
18.3.4
Modular Binding Approach
511
18.3.5
Rule-Based Approaches
512
18.4
Discussion
513
18.4.1
Prediction of Substrate-P-gp Interactions
523
18.4.2
Prediction of ATPase Activity or Intrinsic Transport
513
18.4.3
Prediction of Transport (i.e., Apparent Transport)
513
18.4.4
Prediction of Competition
514
18.4.5
Conclusions
514
References
514
Part Five Drug Development Issues
521
19
Application of the Biopharmaceutics Classification System Now and
in the Future
523
Bertil Abrahamsson
and Hans Lennerna's
19.1
Introduction
524
19.2
Definition of Absorption and Bioavailability of Drugs Following
Oral Administration
527
19.3
Dissolution and Solubility
528
19.4
The Effective Intestinal Permeability (Peff)
535
19.5
Luminal
Degradation and Binding
539
19.6
The Biopharmaceutics Classification System
541
19.6.1
Regulatory Aspects
542
19.6.1.1
Present Situation
541
19.6.1.2
Potential Future Extensions
543
19.6.2
Drug Development Aspects
543
19.6.2.1
Selection of Candidate Drugs
544
19.6.2.2
Choice of Formulation Principle
545
19.6.2.3
In Vitro/In Vivo Correlation
547
19.6.2.4
Food-Drag Interactions
549
19.6.2.5
Quality by Design
552
19.7
Conclusions
552
References
553
20
Prodrugs
559
Bernard Testa
20.1
Introduction
559
20.2
Why Prodrugs?
560
20.2.1
Pharmaceutical Objectives
560
XVI Contents
20.2.2
Pharmacokinetic Objectives
561
20.2.3
Pharmacodynamic Objectives
564
20.3
How Prodrugs?
565
20.3.1
Types of Prodrugs
565
20.3.2
Hurdles in Prodrug Research
567
20.4
Conclusions
568
References
568
21
Modern Delivery Strategies: Physiological Considerations for Orally
Administered Medications
571
Clive
С.
Wilson and Werner Weitschies
21.1
Introduction
571
21.2
The Targets
572
21.3
The Upper GI Tract: Mouth and Esophagus
573
21.3.1
Swallowing the Bitter Pill.
. 575
21.4
Mid-GI Tract: Stomach and Intestine
576
21.4.1
Gastric Inhomogeneity
576
21.4.2
Gastric Emptying
579
21.4.3
Small Intestinal Transit Patterns
581
21
A A Modulation of Transit to Prolong the Absorption Phase
582
21.4.5
Absorption Enhancement
582
21.5
The Lower GI Tract: The Colon
583
21.5.1
Colonie
Transit
584
21.5.2
Time of Dosing
585
21.5.3
Modulating
Colonie
Water
586
21.6
Pathophysiological Effects on Transit
587
21.7
Pathophysiological Effects on Permeability
589
21.8 pH 589
21
Я
Conclusions
590
References
590
22
Nanotechnology for Improved Drug Bioavailability
597
Marjo Yliperttula
and
Arto Uriti
22.1
Introduction
597
22.2
Nanotechnological Systems in Drug Delivery
599
22.2.1
Classification of the Technologies
599
22.2.1.1
Nanocrystals
599
22.2.1.2
Self-Assembling Nanoparticulates
600
22.2.1.3
Processed Nanoparticulates
601
22.2.1.4
Single-Molecule-Based Nanocarriers
601
22.2.2
Pharmaceutical Properties of Nanotechnological Formulations
601
22.2.2.1
Drug-Loading Capacity
601
22.2.2.2
Processing
602
22.2.2.3
Biological Stability
602
22.3
Delivery via Nanotedmologies
603
Contents XVII
22.3.1
Delivery Aspects at Cellular Level
603
22.3.2
Nanosystems for Improved Oral Drug Bioavailability
606
22.3.3
Nanosystems for Improved Local Drug Bioavailability
606
22.4
Key Issues and Future Prospects
608
References
609
Index
613
In order to reach its intended site of action, the drug molecules in every
pill that we swallow must first be absorbed, transported via the blood¬
stream and evade various mechanisms that eliminate drugs from the
body. Those drug properties that determine, for example, its stability in
the gut or its ease of uptake into the bloodstream, are therefore of central
importance in drug development. In fact, many potentially useful drugs
fail because of insufficient availability at the biological target site.
This second edition of the gold standard for industrial research is
thoroughly revised in line with current trends in the field, with all
contributions extensively updated or rewritten. No other publication
offers the same level of treatment on this crucial topic.
In
22
chapters readers can benefit from the key working knowledge
of today's leading pharmaceutical companies, including Pfizer,
AstraZeneca, and Roche. Drug developers from industry and
academia
present all the factors governing drug bioavailaWlity, complete with
practical examples and real-life data.
Part I focuses on solubility and gastrointestinal absorption, while the
second discusses in vitro and in vivo measurements of physicochemical
properties, such as membrane permeability and solubility. Part III is
devoted to metabolism and excretory mechanisms. The much revised
and expanded Part IV surveys current in silico approaches to predict drug
properties needed to estimate the bioavailability of any new drug
candidate. The final part shows new drug development approaches as
well as delivery strategies.
Indispensable for all those working in the pharmaceutical industry,
pharmaceutical and medicinal chemists, and toxicologists.
Han van
de
Waterbeemd studied physical organic chemistry at the Technical University of
Eindhoven, and gained his PhD in medicinal chemistry from the University of Leiden. After an
academic
career at the University of Lausanne with Bernard Testa, he worked for
20
years in the
pharmaceutical industry for Roche, Ffizer and AstraZeneca. His research interests are in optimizing
compound quality using measured and predicted physicochemical and DMPK properties. He has
contributed to
145
research papers and book chapters, and (co-)edited
73
book, and was involved
in organizing conferences and courses to promote medicinal chemistry, with a focus on physico-
chemistry and predictive approaches in drug design. Dr. van
de
Watbrbeemd is on the editorial
board of several journals and of Methods and Principles in Medicinal Chemistry.
Bernard Testa is Emeritus Professor of the University ofLausanne, having served therefor
25
years
as
afilli
professor and head of medicinal chemistry. He has written
5
books and edited
33
others, and
(coj-authored ¡veil over
450
research and review articles in the fields of drug design and drug
metabolism. Between
1594
and
1998,
he was the European Editor of Pharmaceutical Research,
and is now a senior editor of Chemistry and Biodiversity, as well as serving on the editorial boards,
of several leadingjoumals. Professor Testa holds honorary doctoratesfrom the universities of Milan,
Montpellier
and Parma, and is a recipient of the
Nauta
Award on Pharmacochemistry given
by the European
Federation for
Medicinal Chemistry. |
| any_adam_object | 1 |
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| id | DE-604.BV035197740 |
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| indexdate | 2024-07-20T09:57:46Z |
| institution | BVB |
| isbn | 9783527320516 |
| language | English |
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| series | Methods and principles in medicinal chemistry |
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| spelling | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability ed. by Han van de Waterbeemd ... 2., completely rev. ed. Weinheim Wiley-VCH 2009 XXV, 624 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 40 Literaturangaben Biological Availability Drugs Bioavailability Pharmaceutical Preparations administration & dosage Pharmaceutical Preparations metabolism Pharmacokinetics Pharmazeutische Chemie (DE-588)4132158-3 gnd rswk-swf Arzneimittel (DE-588)4003115-9 gnd rswk-swf Bioverfügbarkeit (DE-588)4145660-9 gnd rswk-swf 1\p (DE-588)4143413-4 Aufsatzsammlung gnd-content Pharmazeutische Chemie (DE-588)4132158-3 s Arzneimittel (DE-588)4003115-9 s Bioverfügbarkeit (DE-588)4145660-9 s DE-604 Waterbeemd, Han van de 1954- Sonstige (DE-588)11443963X oth Methods and principles in medicinal chemistry 40 (DE-604)BV035418617 40 text/html http://deposit.dnb.de/cgi-bin/dokserv?id=3113020&prov=M&dok_var=1&dok_ext=htm Inhaltstext http://d-nb.info/988816008/04 Inhaltsverzeichnis Digitalisierung UB Regensburg application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017004234&sequence=000003&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis Digitalisierung UB Regensburg application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017004234&sequence=000004&line_number=0002&func_code=DB_RECORDS&service_type=MEDIA Klappentext 1\p cgwrk 20201028 DE-101 https://d-nb.info/provenance/plan#cgwrk |
| spellingShingle | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability Methods and principles in medicinal chemistry Biological Availability Drugs Bioavailability Pharmaceutical Preparations administration & dosage Pharmaceutical Preparations metabolism Pharmacokinetics Pharmazeutische Chemie (DE-588)4132158-3 gnd Arzneimittel (DE-588)4003115-9 gnd Bioverfügbarkeit (DE-588)4145660-9 gnd |
| subject_GND | (DE-588)4132158-3 (DE-588)4003115-9 (DE-588)4145660-9 (DE-588)4143413-4 |
| title | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability |
| title_auth | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability |
| title_exact_search | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability |
| title_full | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability ed. by Han van de Waterbeemd ... |
| title_fullStr | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability ed. by Han van de Waterbeemd ... |
| title_full_unstemmed | Drug bioavailability estimation of solubility, permeability, absorption and bioavailability ed. by Han van de Waterbeemd ... |
| title_short | Drug bioavailability |
| title_sort | drug bioavailability estimation of solubility permeability absorption and bioavailability |
| title_sub | estimation of solubility, permeability, absorption and bioavailability |
| topic | Biological Availability Drugs Bioavailability Pharmaceutical Preparations administration & dosage Pharmaceutical Preparations metabolism Pharmacokinetics Pharmazeutische Chemie (DE-588)4132158-3 gnd Arzneimittel (DE-588)4003115-9 gnd Bioverfügbarkeit (DE-588)4145660-9 gnd |
| topic_facet | Biological Availability Drugs Bioavailability Pharmaceutical Preparations administration & dosage Pharmaceutical Preparations metabolism Pharmacokinetics Pharmazeutische Chemie Arzneimittel Bioverfügbarkeit Aufsatzsammlung |
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