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 90
EDITED BY
SARA E. ROSENBAUM
Heart Rate (bpm)

70 SECOND EDITION

50
0 10 20 30 40 50
C (mcg/L)

Dose 1 Dose 2
CONTENTS

Preface xix
Contributors xxi

1 Introduction to Pharmacokinetics and Pharmacodynamics 1

Sara E. Rosenbaum

1.1 Introduction: Drugs and Doses, 2

1.2 Introduction to Pharmacodynamics, 3
1.2.1 Drug Effects at the Site of Action, 3
1.2.2 Agonists, Antagonists, and Concentration–Response
Relationships, 6
1.3 Introduction to Pharmacokinetics, 9
1.3.1 Plasma Concentration of Drugs, 9
1.3.2 Processes in Pharmacokinetics, 11
1.4 Dose–Response Relationships, 12
1.5 Therapeutic Range, 14
1.5.1 Determination of the Therapeutic Range, 15
1.6 Summary, 18
Reference, 18

2 Passage of Drugs Through Membranes 19

Sara E. Rosenbaum
2.1 Introduction, 20
2.2 Structure and Properties of Membranes, 20
2.3 Passive Diffusion, 21
2.3.1 Transcellular Passive Diffusion, 23
2.3.2 Paracellular Passive Diffusion, 25
2.4 Carrier-Mediated Processes: Transport Proteins, 26
2.4.1 Uptake Transporters: SLC Superfamily, 27
vii
viii CONTENTS

2.4.2 Efflux Transporters: ABC Superfamily, 29

2.4.3 Characteristics of Transporter Systems, 31
2.4.4 Simulation Exercise, 32
2.4.5 Clinical Examples of Transporter Involvement in Drug
Response, 32
References, 33

3 Drug Administration and Drug Absorption 35

Steven C. Sutton

3.1 Introduction: Local and Systemic Drug Administration, 36

3.2 Routes of Drug Administration, 37
3.2.1 Common Routes of Local Drug Administration, 37
3.2.2 Common Routes of Systemic Drug Administration, 38
3.3 Overview of Oral Absorption, 41
3.3.1 Anatomy and Physiology of the Oral-Gastric-Intestinal Tract
and Transit Time, 41
3.4 Extent of Drug Absorption, 44
3.4.1 Bioavailability Factor, 44
3.4.2 Individual Bioavailability Factors, 45
3.5 Determinants of the Fraction of the Dose Absorbed (F), 46
3.5.1 Disintegration, 46
3.5.2 Dissolution, 46
3.5.3 Formulation Excipients, 50
3.5.4 Adverse Events within the Gastrointestinal Lumen, 50
3.5.5 Transcellular Passive Diffusion, 53
3.5.6 Particulate Uptake, 53
3.5.7 Paracellular Passive Diffusion, 53
3.5.8 Uptake and Efflux Transporters, 54
3.5.9 Presystemic Intestinal Metabolism or Extraction, 58
3.5.10 Presystemic Hepatic Metabolism or Extraction, 60
3.6 Factors Controlling the Rate of Drug Absorption, 61
3.6.1 Dissolution-Controlled Absorption, 63
3.6.2 Membrane Penetration-Controlled Absorption, 63
3.6.3 Overall Rate of Drug Absorption, 63
3.7 Biopharmaceutics Classification System, 64
3.7.1 Intestinal Reserve Length, 64
3.7.2 Biopharmaceutics Classification System (BCS), 64
3.7.3 Biopharmaceutics Drug Disposition Classification System
(BDDCS), 65
3.8 Food Effects, 65
Problems, 66
References, 67

4 Drug Distribution 71
Sara E. Rosenbaum
4.1 Introduction, 72
4.2 Extent of Drug Distribution, 72
4.2.1 Distribution Volumes, 74
 CONTENTS ix

4.2.2 Tissue Binding, Plasma Protein Binding, and Partitioning:

Concentrating Effects, 75
4.2.3 Assessment of the Extent of Drug Distribution: Apparent
Volume of Distribution, 76
4.2.4 Plasma Protein Binding, 82
4.3 Rate of Drug Distribution, 89
4.3.1 Perfusion-Controlled Drug Distribution, 90
4.3.2 Diffusion or Permeability-Controlled Drug Distribution, 93
4.4 Distribution of Drugs to the Central Nervous System, 93
Problems, 96
References, 98

5 Drug Elimination and Clearance 99

Sara E. Rosenbaum

5.1 Introduction, 100

5.1.1 First-Order Elimination, 101
5.1.2 Determinants of the Elimination Rate Constant and the
Half-Life, 102
5.2 Clearance, 102
5.2.1 Definition and Determinants of Clearance, 102
5.2.2 Total Clearance, Renal Clearance, and Hepatic Clearance, 104
5.2.3 Relationships among Clearance, Volume of Distribution,
Elimination Rate Constant, and Half-Life, 105
5.2.4 Primary and Secondary Parameters, 106
5.2.5 Measurement of Total Body Clearance, 106
5.3 Renal Clearance, 108
5.3.1 Glomerular Filtration, 109
5.3.2 Tubular Secretion, 110
5.3.3 Tubular Reabsorption, 113
5.3.4 Putting Meaning into the Value of Renal Clearance, 114
5.3.5 Measurement of Renal Clearance, 115
5.3.6 Fraction of the Dose Excreted Unchanged, 118
5.4 Hepatic Elimination and Clearance, 119
5.4.1 Phase I and Phase II Metabolism, 120
5.4.2 The Cytochrome P450 Enzyme System, 121
5.4.3 Glucuronidation, 122
5.4.4 Metabolism-Based Drug–Drug Interactions, 122
5.4.5 Hepatic Drug Transporters and Drug–Drug Interactions, 125
5.4.6 Kinetics of Drug Metabolism, 127
5.4.7 Hepatic Clearance and Related Parameters, 128
Problems, 139
References, 142

6 Compartmental Models in Pharmacokinetics 145

Sara E. Rosenbaum
6.1 Introduction, 146
x CONTENTS

6.2 Expressions for Component Parts of the Dose–Plasma Concentration

Relationship, 146
6.2.1 Effective Dose, 146
6.2.2 Rate of Drug Absorption, 147
6.2.3 Rate of Drug Elimination, 148
6.2.4 Rate of Drug Distribution, 148
6.3 Putting Everything Together: Compartments and Models, 149
6.3.1 One-Compartment Model, 149
6.3.2 Two-Compartment Model, 150
6.3.3 Three-Compartment Model, 150
6.4 Examples of Complete Compartment Models, 152
6.4.1 Intravenous Bolus Injection in a One-Compartment Model
with First-Order Elimination, 152
6.4.2 Intravenous Bolus Injection in a Two-Compartment Model
with First-Order Elimination, 153
6.4.3 First-Order Absorption in a Two-Compartment Model with
First-Order Elimination, 154
6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics, 155
6.6 Selecting and Applying Models, 156
Problems, 157
Suggested Readings, 157
7 Pharmacokinetics of an Intravenous Bolus Injection in a
One-Compartment Model 159
Sara E. Rosenbaum
7.1 Introduction, 160
7.2 One-Compartment Model, 160
7.3 Pharmacokinetic Equations, 162
7.3.1 Basic Equation, 162
7.3.2 Half-Life, 163
7.3.3 Time to Eliminate a Dose, 163
7.4 Simulation Exercise, 163
7.5 Application of the Model, 165
7.5.1 Predicting Plasma Concentrations, 165
7.5.2 Duration of Action, 166
7.5.3 Value of a Dose to Give a Desired Initial Plasma
Concentration, 167
7.5.4 Intravenous Loading Dose, 167
7.6 Determination of Pharmacokinetic Parameters Experimentally, 168
7.6.1 Study Design for the Determination of Parameters, 168
7.6.2 Pharmacokinetic Analysis, 169
7.7 Pharmacokinetic Analysis in Clinical Practice, 173
Problems, 174
Suggested Reading, 176
8 Pharmacokinetics of an Intravenous Bolus Injection in a
Two-Compartment Model 177
Sara E. Rosenbaum

8.1 Introduction, 178

 CONTENTS xi

8.2 Tissue and Compartmental Distribution of a Drug, 179

8.2.1 Drug Distribution to the Tissues, 179
8.2.2 Compartmental Distribution of a Drug, 180
8.3 Basic Equation, 181
8.3.1 Distribution: A, α, and the Distribution t1/2 , 182
8.3.2 Elimination: B, β, and the β t1/2 , 182
8.4 Relationship Between Macro and Micro Rate Constants, 183
8.5 Primary Pharmacokinetic Parameters, 183
8.5.1 Clearance, 184
8.5.2 Distribution Clearance, 184
8.5.3 Volume of Distribution, 186
8.6 Simulation Exercise, 188
8.7 Determination of the Pharmacokinetic Parameters of the
Two-Compartment Model, 191
8.7.1 Determination of Intercepts and Macro Rate Constants, 191
8.7.2 Determination of the Micro Rate Constants: k12 , k21 , and k10 , 193
8.7.3 Determination of the Primary Pharmacokinetic Parameters, 193
8.8 Clinical Application of the Two-Compartment Model, 194
8.8.1 Measurement of the Elimination Half-Life in the
Postdistribution Phase, 194
8.8.2 Determination of the Loading Dose, 195
8.8.3 Evaluation of a Dose: Monitoring Plasma Concentrations and
Patient Response, 197
Problems, 197
Suggested Readings, 199

9 Pharmacokinetics of Extravascular Drug Administration 201

Dr. Steven C. Sutton
9.1 Introduction, 202
9.2 First-Order Absorption in a One-Compartment Model, 203
9.2.1 Model and Equations, 203
9.2.2 Parameter Determination, 205
9.2.3 Absorption Lag Time, 210
9.2.4 Flip-Flop Model and Sustained-Release Preparations, 212
9.2.5 Determinants of Tmax and Cmax , 212
9.3 Modified Release and Gastric Retention Formulations, 214
9.3.1 Impact of the Stomach, 214
9.3.2 Moisture in the Gastrointestinal Tract, 215
9.4 Bioavailability, 215
9.4.1 Bioavailability Parameters, 215
9.4.2 Absolute Bioavailability, 217
9.4.3 Relative Bioavailability, 217
9.4.4 Bioequivalence, 217
9.4.5 Single-Dose Crossover Parallel and Steady-State Study
Designs, 219
9.4.6 Example Bioavailability Analysis, 219
9.5 In Vitro-In Vivo Correlation, 219
9.5.1 Definitions, 219
xii CONTENTS

9.5.2 Assumptions, 220

9.5.3 Utility, 220
9.5.4 Immediate Release IVIVC, 220
9.5.5 Modified Release IVIVC, 221
9.6 Simulation Exercise, 222
Problems, 223
References, 224

10 Introduction to Noncompartmental Analysis 225

Sara E. Rosenbaum

10.1 Introduction, 225

10.2 Mean Residence Time, 226
10.3 Determination of Other Important Pharmacokinetic Parameters, 229
10.4 Different Routes of Administration, 231
10.5 Application of Noncompartmental Analysis to Clinical Studies, 232
Problems, 234

11 Pharmacokinetics of Intravenous Infusion in a One-Compartment Model 237

Sara E. Rosenbaum
11.1 Introduction, 238
11.2 Model and Equations, 239
11.2.1 Basic Equation, 239
11.2.2 Application of the Basic Equation, 241
11.2.3 Simulation Exercise: Part 1, 241
11.3 Steady-State Plasma Concentration, 242
11.3.1 Equation for Steady-State Plasma Concentrations, 242
11.3.2 Application of the Equation, 242
11.3.3 Basic Formula Revisited, 243
11.3.4 Factors Controlling Steady-State Plasma Concentration, 243
11.3.5 Time to Steady State, 244
11.3.6 Simulation Exercise: Part 2, 245
11.4 Loading Dose, 246
11.4.1 Loading-Dose Equation, 246
11.4.2 Simulation Exercise: Part 3, 248
11.5 Termination of Infusion, 248
11.5.1 Equations for Termination Before and After Steady State, 248
11.5.2 Simulation Exercise: Part 4, 249
11.6 Individualization of Dosing Regimens, 249
11.6.1 Initial Doses, 249
11.6.2 Monitoring and Individualizing Therapy, 250
Problems, 252

12 Multiple Intravenous Bolus Injections in the One-Compartment Model 255

Sara E. Rosenbaum

12.1 Introduction, 256

12.2 Terms and Symbols Used in Multiple-Dosing Equations, 257
 CONTENTS xiii

12.3 Monoexponential Decay During a Dosing Interval, 259

12.3.1 Calculation of Dosing Interval to Give Specific Steady-State
Peaks and Troughs, 260
12.4 Basic Pharmacokinetic Equations for Multiple Doses, 260
12.4.1 Principle of Superposition, 260
12.4.2 Equations that Apply Before Steady State, 261
12.5 Steady State, 262
12.5.1 Steady-State Equations, 263
12.5.2 Average Plasma Concentration at Steady State, 264
12.5.3 Fluctuation, 267
12.5.4 Accumulation, 267
12.5.5 Time to Reach Steady State, 269
12.5.6 Loading Dose, 270
12.6 Basic Formula Revisited, 270
12.7 Pharmacokinetic-Guided Dosing Regimen Design, 270
12.7.1 General Considerations for Selection of the Dosing Interval, 270
12.7.2 Protocols for Pharmacokinetic-Guided Dosing Regimens, 272
12.8 Simulation Exercise, 276
Problems, 277
Reference, 278

13 Multiple Intermittent Infusions 279

Sara E. Rosenbaum

13.1 Introduction, 279

13.2 Steady-State Equations for Multiple Intermittent Infusions, 281
13.3 Monoexponential Decay During a Dosing Interval: Determination of
Peaks, Troughs, and Elimination Half-Life, 284
13.3.1 Determination of Half-Life, 284
13.3.2 Determination of Peaks and Troughs, 286
13.4 Determination of the Volume of Distribution, 286
13.5 Individualization of Dosing Regimens, 289
13.6 Simulation, 289
Problems, 290

14 Multiple Oral Doses 293

Sara E. Rosenbaum

14.1 Introduction, 293

14.2 Steady-State Equations, 294
14.2.1 Time to Peak Steady-State Plasma Concentration, 295
14.2.2 Maximum Steady-State Plasma Concentration, 296
14.2.3 Minimum Steady-State Plasma Concentration, 296
14.2.4 Average Steady-State Plasma Concentration, 296
14.2.5 Overall Effect of Absorption Parameters on a Steady-State
Dosing Interval, 297
14.3 Equations Used Clinically to Individualize Oral Doses, 298
14.3.1 Protocol to Select an Appropriate Equation, 298
14.4 Simulation Exercise, 300
References, 301
xiv CONTENTS

15 Nonlinear Pharmacokinetics 303

Sara E. Rosenbaum

15.1 Linear Pharmacokinetics, 304

15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and
Elimination, 306
15.3 Pharmacokinetics of Capacity-Limited Metabolism, 307
15.3.1 Kinetics of Enzymatic Processes, 307
15.3.2 Plasma Concentration–Time Profile, 309
15.4 Phenytoin, 310
15.4.1 Basic Equation for Steady State, 311
15.4.2 Estimation of Doses and Plasma Concentrations, 313
15.4.3 Influence of Km and Vmax and Factors That Affect These
Parameters, 314
15.4.4 Time to Eliminate the Drug, 316
15.4.5 Time to Reach Steady State, 317
15.4.6 Individualization of Doses of Phenytoin, 318
Problems, 321
References, 322

16 Introduction to Pharmacogenetics 323

Dr. Daniel Brazeau
16.1 Introduction, 324
16.2 Genetics Primer, 324
16.2.1 Basic Terminology: Genes, Alleles, Loci, and Polymorphism, 324
16.2.2 Population Genetics: Allele and Genotype Frequencies, 326
16.2.3 Quantitative Genetics and Complex Traits, 327
16.3 Pharmacogenetics, 328
16.3.1 Pharmacogenetics of Drug-Metabolizing Enzymes, 330
16.3.2 Pharmacogenetics of Drug Transporters, 333
16.4 Genetics and Pharmacodynamics, 334
16.4.1 Drug Target Pharmacogenetics, 334
16.5 Summary, 335
Reference, 335
Suggested Readings, 335

17 Models Used to Predict Drug–Drug Interactions for Orally

Administered Drugs 337
Sara E. Rosenbaum

17.1 Introduction, 338

17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism
Based on In Vitro Data, 340
17.2.1 Reversible Inhibition, 340
17.2.2 Time-Dependent Inhibition, 341
17.2.3 Induction, 345
17.3 Surrogate In Vivo Values for the Unbound Concentration of the
Perpetrator at the Site of Action, 345
17.3.1 Surrogate Measures of Hepatic Inhibitor and Inducer
Concentrations, 346
 CONTENTS xv

17.3.2 Surrogate Measures of Intestinal Inhibitor and Inducer

Concentrations, 346
17.4 Models Used to Predict DDIs In Vivo, 347
17.4.1 Introduction, 347
17.4.2 Basic Predictive Models: R Values, 348
17.4.3 Predictive Models Incorporating Parallel Pathways of
Elimination (fm), 350
17.4.4 Models Incorporating Intestinal Extraction, 354
17.4.5 Models Combining Multiple Actions of Perpetrators, 358
17.5 Predictive Models for Transporter-Based DDIs, 359
17.5.1 Kinetics of Drug Transporters, 359
17.6 Application of Physiologically Based Pharmacokinetic Models to DDI
Prediction: The Dynamic Approach, 362
17.7 Conclusion, 362
Problems, 363
References, 364

18 Introduction to Physiologically Based Pharmacokinetic Modeling 367

Sara E. Rosenbaum
18.1 Introduction, 368
18.2 Components of PBPK Models, 369
18.3 Equations for PBPK Models, 369
18.4 Building a PBPK Model, 373
18.5 Simulations, 377
18.6 Estimation of Human Drug-Specific Parameters, 378
18.6.1 Tissue Plasma Partition Coefficient, 379
18.6.2 Volume of Distribution, 379
18.6.3 Clearance, 380
18.7 More Detailed PBPK Models, 381
18.7.1 Permeability-Limited Distribution, 381
18.7.2 Drug Transporters, 383
18.7.3 Models for Oral Absorption, 386
18.7.4 Reduced Models, 387
18.8 Application of PBPK Models, 387
References, 388

19 Introduction to Pharmacodynamic Models and Integrated

Pharmacokinetic–Pharmacodynamic Models 391
Drs. Diane Mould and Paul Hutson
19.1 Introduction, 392
19.2 Classic Pharmacodynamic Models Based on Receptor Theory, 393
19.2.1 Receptor Binding, 394
19.2.2 Concentration-Response Models, 395
19.3 Direct Effect Pharmacodynamic Models, 402
19.3.1 Emax and Sigmoidal Emax Models, 402
19.3.2 Inhibitory Imax and Sigmoidal Imax Models, 404
19.3.3 Linear Adaptations of the Emax and Imax Model, 404
xvi CONTENTS

19.4 Integrated PK–PD Models: Intravenous Bolus Injection in the

One-Compartment Mode and the Sigmoidal Emax Model, 406
19.4.1 Simulation Exercise, 409
19.5 Pharmacodynamic Drug–Drug Interactions, 410
19.5.1 Simulation Exercise, 410
Problems, 411
References, 412

20 Semimechanistic Pharmacokinetic–Pharmacodynamic Models 413

Drs. Diane Mould and Paul Hutson
20.1 Introduction, 414
20.2 Hysteresis and the Effect Compartment, 416
20.2.1 Simulation Exercise, 419
20.3 Physiological Turnover Models and Their Characteristics, 419
20.3.1 Points of Drug Action, 421
20.3.2 System Recovery After Change in Baseline Value, 421
20.4 Indirect Effect Models, 422
20.4.1 Introduction, 422
20.4.2 Characteristics of Indirect Effect Drug Responses, 424
20.4.3 Characteristics of Indirect Effect Models Illustrated Using
Model I, 426
20.5 Other Indirect Effect Models, 432
20.5.1 Transit Compartment Models, 435
20.5.2 Model for Hematological Toxicity of Anticancer Drugs, 439
20.5.3 Alternate Parameterizations of Transit Models, 442
20.6 Models of Tolerance, 442
20.6.1 Introduction to Pharmacologic Tolerance, 442
20.6.2 Counter-Regulatory Force Tolerance Model, 444
20.6.3 Precursor Pool Model of Tolerance, 447
20.7 Irreversible Drug Effects, 450
20.7.1 Application of the Turnover Model to Irreversible Drug
Action, 450
20.8 Disease Progression Models, 452
20.8.1 Drug Pharmacokinetics, 452
20.8.2 Pharmacodynamics, 452
20.8.3 Disease Activity Models, 453
20.8.4 Disease Progression Models, 453
Problems, 459
References, 465

Appendix A Review of Exponents and Logarithms 469

Sara E. Rosenbaum
A.1 Exponents, 469
A.2 Logarithms: Log and Ln, 470
A.3 Performing Calculations in the Logarithmic Domain, 471
A.3.1 Multiplication, 471
A.3.2 Division, 472
 CONTENTS xvii

A.3.3 Reciprocals, 472

A.3.4 Exponents, 472
A.4 Calculations Using Exponential Expressions and
Logarithms, 472
A.5 Decay Function: e−kt , 474
A.6 Growth Function: 1 − e−kt , 475
A.7 Decay Function in Pharmacokinetics, 475
Problems, 476

Appendix B Rates of Processes 479

Sara E. Rosenbaum

B.1 Introduction, 479

B.2 Order of a Rate Process, 480
B.3 Zero-Order Processes, 480
B.3.1 Equation for Zero-Order Filling, 480
B.3.2 Equation for Zero-Order Emptying, 481
B.3.3 Time for Zero-Order Emptying to Go to 50%
Completion, 481
B.4 First-Order Processes, 482
B.4.1 Equation for a First-Order Process, 482
B.4.2 Time for 50% Completion: the Half-Life, 483
B.5 Comparison of Zero- and First-Order Processes, 484
B.6 Detailed Example of First-Order Decay in
Pharmacokinetics, 484
B.6.1 Equations and Semilogarithmic Plots, 484
B.6.2 Half-Life, 485
B.6.3 Fraction or Percent Completion of a First-Order
Process Using First-Order Elimination as an
Example, 485
B.7 Examples of the Application of First-Order Kinetics to
Pharmacokinetics, 487

Appendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 489

Sara E. Rosenbaum
C.1 Measurement of AUC and Clearance, 489
C.1.1 Trapezoidal Rule, 490
C.1.2 Excel Spreadsheet to Determine AUC0→∞ and
Clearance, 491
C.2 Analysis of Data from an Intravenous Bolus Injection in a
One-Compartment Model, 494
C.3 Analysis of Data from an Intravenous Bolus Injection in a
Two-Compartment Model, 496
C.4 Analysis of Oral Data in a One-Compartment Model, 498
C.5 Noncompartmental Analysis of Oral Data, 501

Appendix D Derivation of Equations for Multiple Intravenous Bolus

Injections 505
Sara E. Rosenbaum
D.1 Assumptions, 505
xviii CONTENTS

D.2 Basic Equation for Plasma Concentration After Multiple

Intravenous Bolus Injections, 505
D.3 Steady-State Equations, 508

Appendix E Enzyme Kinetics: Michaelis–Menten Equation and Models for

Inhibitors and Inducers of Drug Metabolism 509
Sara E. Rosenbaum and Roberta S. King
E.1 Kinetics of Drug Metabolism: The Michaelis–Menten
Model, 510
E.1.1 Overview, 510
E.1.2 Assumptions for Validity of Michaelis–Menten
Model, 510
E.1.3 Km and Vmax, 511
E.1.4 Derivation of the Michaelis–Menten Equation, 511
E.1.5 Summary, Practical Considerations, and
Interpretations, 513
E.1.6 Relationship Between Intrinsic Clearance and the
Michaelis–Menten Parameters, 514
E.2 Effect of Perpetrators of DDI on Enzyme Kinetics and
Intrinsic Clearance, 515
E.2.1 Reversible Inhibition, 515
E.2.2 Time-Dependent Inhibition, 518
E.2.3 Enzyme Induction, 524
References, 526

Appendix F Summary of the Properties of the Fictitious Drugs Used in

the Text 527
Sara E. Rosenbaum

Appendix G Computer Simulation Models 529

Sara E. Rosenbaum

Glossary of Terms 531

Index 537
PREFACE

The goal of the second edition of Basic Pharmacokinetics and Pharmacodynamics is to

update and strengthen existing chapters of the book and to add additional chapters in
response to recent trends in the application of pharmacokinetics and pharmacodynamics
in clinical practice and pharmaceutical research.
Notable areas of update and expansion include both the text and the interactive computer
models associated with drug transporters and hepatic clearance. Additionally, the chapters
on drug absorption/bioavailability and pharmacodynamics have been updated, expanded
and strengthened to reflect the importance of these topics and the need to cover the material
both comprehensively and in a manner compatible with their present application. I felt
that these areas would be most effectively strengthened by experts in each of the fields.
To this end, I am delighted that Dr. Steven Sutton, who has had extensive experience as a
researcher in the pharmaceutical industry and as an educator at the College of Pharmacy,
University of New England, agreed to take over Chapters 3 and 9 that cover drug absorption
and bioavailability. I am also delighted that Drs. Diane Mould and Paul Hutson agreed to
revamp and expand the chapters on pharmacodynamics (Chapters 19 and 20). Dr. Mould of
Projections Research Inc is a well-known pharmacokinetic and pharmacodynamic modeler,
who has extensive experience in the application of pharmacodynamic models. Dr. Hutson
from University of Wisconsin, School of Pharmacy, is similarly experienced and was able
to provide an academic perspective to the overhaul of this material.
Owing to the increasing prominence of personalized and precision medicine, it has
become important that clinical pharmacists and researchers in pharmaceutical fields have
a basic knowledge of pharmacogenomics. Dr. Daniel Brazeau, an experienced educator
and researcher in this area from the College of Pharmacy, University of New England, gra-
ciously agreed to write an introductory chapter on pharmacogenetics for the second edition.
In response to the increasing use and diverse application of physiologically based pharma-
cokinetic (PBPK) modeling that has occurred over the last 15 years, it has become essen-
tial for modern students of pharmacokinetics to have a foundation in this topic. Chapter
18 introduces PBPK models and describes how they are built and applied. The third new
chapter in the second edition presents the predictive models used to evaluate drug–drug

xix
xx PREFACE

interaction (DDI) risk using in vitro data. These models are used increasingly by pharma-
ceutical companies and drug regulators to try to reduce the large health risks and costs posed
by DDIs. While not all readers of the book will need to apply these models profession-
ally, an understanding of this topic will allow students to better understand and appreciate
the mechanism, characteristics, and varied outcome of DDIs. Finally, in order to provide
interested students with a foundation to this latter chapter, the second edition includes an
appendix on basic enzyme kinetics and the mathematical basis of the predictive models.
My colleague at the College of Pharmacy, Dr. Roberta King, an expert in drug metabolism,
collaborated in the preparation of this material. Each of the new chapters is supported by
new interactive computer models.
It is hoped that the second edition of this textbook provides a comprehensive and thor-
ough presentation of all essential topics in the contemporary application of pharmacoki-
netics and pharmacodynamics. While not all chapters will be necessary for the immediate
needs of all audiences, collectively the book should serve as a valuable reference for the
future.
I would like to thank the many scientists who generously gave of their time and provided
me with information and input in many areas. I would especially like to thank Dr. Karthik
Venkatakrishnan for his valuable input on the chapter on predictive models for DDIs. I
would also like to thank and recognize the wonderful work of Pragati Nahar who prepared
the custom color figures in the book, including the figure used on the cover. I would also
like to thank many undergraduate and graduate students at URI who helped in a variety
of ways especially Jamie Chung who provided valuable support for the preparation of the
materials, and Benjamin Barlock and Rohitash Jamwal for their input in the creation of the
simulation models. Finally, I would like to thank Jonathan Rose at Wiley for his patience,
understanding, and responsiveness in the preparation of this edition.
CONTRIBUTORS

Daniel Brazeau Daniel Brazeau is a Research Associate Professor at the University of

New England. He holds joint appointments in the Department of Pharmaceutical Sciences
in the College of Pharmacy and Department of Biomedical Sciences in the College of Osteo-
pathic Medicine. Dr. Brazeau is a Director of UNE’s Genomics Core, a research training
core providing the expertise, technologies and most importantly, training support for faculty
and students. He received his B.S. and M.S. in Biology from the University of Toledo and
earned his Ph.D. in Biological Sciences (1989) from the University at Buffalo. After com-
pleting postdoctoral training in population genetics at the University of Houston, he was
a Research Assistant Professor in the Department of Zoology at the University of Florida
and Director of the University of Florida’s Genetic Analysis Laboratory in the Interdisci-
plinary Research Center for Biotechnology. For 10 years prior to joining UNE, he was a
Research Associate Professor in the Department of Pharmaceutical Sciences at the Univer-
sity at Buffalo and Director of the University at Buffalo’s Pharmaceutical Genetics Labora-
tory. Dr. Brazeau’s research interests involve the areas of population molecular genetics and
genomics. He teaches courses in molecular genetics methodologies and a required course
in pharmacogenomics for graduate and pharmacy professional students. Dr. Brazeau is also
a participating scientist in the National Science Foundation’s Geneticist-Educator Network
Alliances (GENA) working with high school science teachers to incorporate genetics into
the classroom.

Paul Hutson Paul Hutson, whose baccalaureate and master’s degrees are in biochem-
istry and chemistry, respectively, completed an oncology/pharmacokinetics fellowship at
St. Jude Children’s Research Hospital in Memphis. He was a Faculty Member at the Uni-
versity of Illinois for 5 years before moving to the University of Wisconsin School of Phar-
macy in Madison in 1988. He now practices pharmacy with the oncology and palliative
care group at the UW Hospital and Clinics and is an Associate Member of the UW Car-
bone Cancer Center. His three course offerings at the School of Pharmacy are Clinical Phar-
macokinetics, Pediatric Pharmacotherapy, and Dietary Supplements, and he supervises an
Advanced Pharmacy Practice Experience (APPE) in basic pharmacometrics. Dr. Hutson

xxi
xxii CONTRIBUTORS

provides pharmacometric modeling services to the pharmaceutical industry and to Univer-

sity of Wisconsin—Madison investigators through its CTSA-funded Institute for Clinical
and Translational Research.

Roberta S. King Roberta S. King is an Associate Professor at the University of Rhode

Island, College of Pharmacy. Her research expertise is in metabolism and enzymology
focusing on individual variation in activity of the drug-metabolizing enzymes. She teaches
Drug Metabolism and Structure-based Drug Design.

Dr. Mould Dr. Mould obtained her bachelors degree at Stevens Institute of Technology
in 1984 in Chemistry and Chemical Biology. She received her Ph.D. in Pharmaceutics
and Pharmaceutical Chemistry at The Ohio State University (OSU) in 1989. She spent
26 years as a pharmacokineticist in industry where she specialized in population pharma-
cokinetic/pharmacodynamic modeling and was an Associate Research Professor at George-
town University. She has conducted population PK/PD analyses of hematopoietic agents,
monoclonal antibodies, anticancer and antiviral agents, antipsychotic, cardiovascular, and
sedative/hypnotic agents. Dr Mould is involved in clinical trial simulation and optimal study
design in drug development. She was a member of the Scientific Advisory Group for Phar-
Sight, where she assisted in development of clinical trial simulation software.
Currently, Dr Mould is President of Projections Research Inc., a consulting company
offering pharmacokinetic and pharmacometric services. She is also the founder of iDose
LLC, a company that develops systems to individualize doses of drugs that are difficult to
manage. She has published 62 peer-reviewed articles, 16 book chapters, made 97 national
and international presentations, and presented six podium sessions on advanced modeling
and simulation approaches. Dr Mould has authored 97 posters at both national and interna-
tional meetings. She is an Adjunct Professor at the University of Rhode Island (URI), OSU,
and the University of Florida, and teaches an annual class on disease progression modeling
at the National Institutes of Health. Dr Mould taught nine courses (OSU, URI, and SUNY
Buffalo) on specialized aspects of population pharmacokinetic and dynamic modeling. She
is a member of the editorial board for Journal of Pharmacokinetics and Pharmacodynam-
ics, Clinical Pharmacology and Therapeutics, and Clinical Pharmacology and Therapeu-
tics Pharmacometrics and Systems Pharmacology. Dr. Mould is a member of the Board
of Regents for the American College of Clinical Pharmacology and is a Chairman of the
Publications committee for this organization. She is a Fellow of the American College of
Clinical Pharmacology and the American Association of Pharmaceutical Sciences.

Steven C. Sutton Steven (Steev) C. Sutton, B.S. Pharmacy, Ph.D., University of New
England, Portland, Maine Dr. Sutton is an Associate Professor and Chair of Pharmaceu-
tics, College of Pharmacy, University of New England in Portland, Maine. He received his
B.S. in Pharmacy from Massachusetts College of Pharmacy and a Ph.D. in Pharmaceutical
Sciences from the State University of New York at Buffalo, New York. Dr Sutton began
his career in the pharmaceutical industry working for CIBA-Geigy in Ardsley, NY (now
Novartis), for INTERx in Lawrence, KS (then a part of Merck), and for Pfizer in Groton, CT,
before embarking in a second career—that of academia—at the University of New England
College of Pharmacy in Portland in 2009. Dr. Sutton founded the AAPS Oral Absorption
Focus Group and in 2003, he became a Fellow of the AAPS. His research interests include
predicting active pharmaceutical ingredient concentration–time profile in human after oral
administration from chemical structure, modeling, and simulation of oral absorption of low
permeability and/or low aqueous soluble compounds, in vitro—in vivo correlation of orally
 CONTRIBUTORS xxiii

administered controlled release dosage forms, species differences in gastrointestinal (GI)

physiology, and transport of nanoparticles across the GI epithelium. Dr. Sutton has authored
or coauthored over 120 book chapters, abstracts of work in progress, invited presentations,
and patents.
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of Exploration
Team
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.

Title: Exploration Team

Author: Murray Leinster

Illustrator: Ed Emshwiller

Release date: August 11, 2022 [eBook #68730]

Language: English

Original publication: United States: Street & Smith Publications, Inc,

1956

Credits: Greg Weeks, Mary Meehan and the Online Distributed

Proofreading Team at http://www.pgdp.net

*** START OF THE PROJECT GUTENBERG EBOOK

EXPLORATION TEAM ***
EXPLORATION TEAM
 BY MURRAY LEINSTER

Illustrated by Emsh

[Transcriber's Note: This etext was produced from

Astounding Science Fiction, March 1956.
Extensive research did not uncover any evidence that
the U.S. copyright on this publication was renewed.]
 I
The nearer moon went by overhead. It was jagged and irregular in
shape, and was probably a captured asteroid. Huyghens had seen it
often enough, so he did not go out of his quarters to watch it hurtle
across the sky with seemingly the speed of an atmosphere-flier,
occulting the stars as it went. Instead, he sweated over paper work,
which should have been odd because he was technically a felon and
all his labors on Loren Two felonious. It was odd, too, for a man to do
paper work in a room with steel shutters and a huge bald eagle—
untethered—dozing on a three-inch perch set in the wall. But paper
work was not Huyghens' real task. His only assistant had tangled with
a night-walker and the furtive Kodius Company ships had taken him
away to where Kodius Company ships came from. Huyghens had to
do two men's work in loneliness. To his knowledge, he was the only
man in this solar system.
Below him, there were snufflings. Sitka Pete got up heavily and
padded to his water pan. He lapped the refrigerated water and
sneezed violently. Sourdough Charley waked and complained in a
rumbling growl. There were divers other rumblings and mutterings
below. Huyghens called reassuringly, "Easy there!" and went on with
his work. He finished a climate report, and fed figures to a computer,
and while it hummed over them he entered the inventory totals in the
station log, showing what supplies remained. Then he began to write
up the log proper.
"Sitka Pete," he wrote, "has apparently solved the problem of killing
individual sphexes. He has learned that it doesn't do to hug them and
that his claws can't penetrate their hide—not the top hide, anyhow.
Today Semper notified us that a pack of sphexes had found the
scent-trail to the station. Sitka hid down-wind until they arrived. Then
he charged from the rear and brought his paws together on both
sides of a sphex's head in a terrific pair of slaps. It must have been
like two twelve-inch shells arriving from opposite directions at the
same time. It must have scrambled the sphex's brains as if they were
eggs. It dropped dead. He killed two more with such mighty pairs of
wallops. Sourdough Charley watched, grunting, and when the
sphexes turned on Sitka, he charged in his turn. I, of course, couldn't
shoot too close to him, so he might have fared badly but that Faro
Nell came pouring out of the bear quarters to help. The diversion
enabled Sitka Pete to resume the use of his new technic, towering on
his hind legs and swinging his paws in the new and grisly fashion.
The fight ended promptly. Semper flew and screamed above the
scrap, but as usual did not join in. Note: Nugget, the cub, tried to mix
in but his mother cuffed him out of the way. Sourdough and Sitka
ignored him as usual. Kodius Champion's genes are sound!"
The noises of the night went on outside. There were notes like organ
tones—song lizards. There were the tittering giggling cries of night-
walkers—not to be tittered back at. There were sounds like tack
hammers, and doors closing, and from every direction came noises
like hiccups in various keys. These were made by the improbable
small creatures which on Loren Two took the place of insects.
Huyghens wrote out:
"Sitka seemed ruffled when the fight was over. He painstakingly used
his trick on every dead or wounded sphex, except those he'd killed
with it, lifting up their heads for his pile-driverlike blows from two
directions at once, as if to show Sourdough how it was done. There
was much grunting as they hauled the carcasses to the incinerator. It
almost seemed—"

The arrival bell clanged, and Huyghens jerked up his head to stare at
it. Semper, the eagle, opened icy eyes. He blinked.
Noises. There was a long, deep, contented snore from below.
Something shrieked, out in the jungle. Hiccups. Clatterings, and
organ notes—
The bell clanged again. It was a notice that a ship aloft somewhere
had picked up the beacon beam—which only Kodius Company ships
should know about—and was communicating for a landing. But there
shouldn't be any ships in this solar system just now! This was the only
habitable planet of the sun, and it had been officially declared
uninhabitable by reason of inimical animal life. Which meant sphexes.
Therefore no colony was permitted, and the Kodius Company broke
the law. And there were few graver crimes than unauthorized
occupation of a new planet.
The bell clanged a third time. Huyghens swore. His hand went out to
cut off the beacon—but that would be useless. Radar would have
fixed it and tied it in with physical features like the nearby sea and the
Sere Plateau. The ship could find the place, anyhow, and descend by
day-light.
"The devil!" said Huyghens. But he waited yet again for the bell to
ring. A Kodius Company ship would double-ring to reassure him. But
there shouldn't be a Kodius Company ship for months.
The bell clanged singly. The space phone dial flickered and a voice
came out of it, tinny from stratospheric distortion:
"Calling ground! Calling ground! Crete Line ship Odysseus calling
ground on Loren Two. Landing one passenger by boat. Put on your
field lights."
Huyghens' mouth dropped open. A Kodius Company ship would be
welcome. A Colonial Survey ship would be extremely unwelcome,
because it would destroy the colony and Sitka and Sourdough and
Faro Nell and Nugget—and Semper—and carry Huyghens off to be
tried for unauthorized colonization and all that it implied.
But a commercial ship, landing one passenger by boat—There were
simply no circumstances under which that would happen. Not to an
unknown, illegal colony. Not to a furtive station!
Huyghens flicked on the landing-field lights. He saw the glare in the
field outside. Then he stood up and prepared to take the measures
required by discovery. He packed the paper work he'd been doing
into the disposal safe. He gathered up all personal documents and
tossed them in. Every record, every bit of evidence that the Kodius
Company maintained this station went into the safe. He slammed the
door. He touched his finger to the disposal button, which would
destroy the contents and melt down even the ashes past their
possible use for evidence in court.
Then he hesitated. If it were a Survey ship, the button had to be
pressed and he must resign himself to a long term in prison. But a
Crete Line ship—if the space phone told the truth—was not
threatening. It was simply unbelievable.
He shook his head. He got into travel garb and armed himself. He
went down into the bear quarters, turning on lights as he went. There
were startled snufflings and Sitka Pete reared himself very absurdly
to a sitting position to blink at him. Sourdough Charley lay on his back
with his legs in the air. He'd found it cooler, sleeping that way. He
rolled over with a thump. He made snorting sounds which somehow
sounded cordial. Faro Nell padded to the door of her separate
apartment—assigned her so that Nugget would not be under-foot to
irritate the big males.
Huyghens, as the human population of Loren Two, faced the work
force, fighting force, and—with Nugget—four-fifths of the terrestrial
nonhuman population of the planet. They were mutated Kodiak
bears, descendants of that Kodius Champion for whom the Kodius
Company was named. Sitka Pete was a good twenty-two hundred
pounds of lumbering, intelligent carnivore. Sourdough Charley would
weigh within a hundred pounds of that figure. Faro Nell was eighteen
hundred pounds of female charm—and ferocity. Then Nugget poked
his muzzle around his mother's furry rump to see what was toward,
and he was six hundred pounds of ursine infancy. The animals looked
at Huyghens expectantly. If he'd had Semper riding on his shoulder,
they'd have known what was expected of them.
"Let's go," said Huyghens. "It's dark outside, but somebody's coming.
And it may be bad!"

He unfastened the outer door of the bear quarters. Sitka Pete went
charging clumsily through it. A forth-right charge was the best way to
develop any situation—if one was an oversized male Kodiak bear.
Sourdough went lumbering after him. There was nothing hostile
immediately outside. Sitka stood up on his hind legs—he reared up a
solid twelve feet—and sniffed the air. Sourdough methodically
lumbered to one side and then the other, sniffing in his turn. Nell
came out, nine-tenths of a ton of daintiness, and rumbled
admonitorily at Nugget, who trailed her closely. Huyghens stood in
the doorway, his night-sighted gun ready. He felt uncomfortable at
sending the bears ahead into a Loren Two jungle at night. But they
were qualified to scent danger, and he was not.
The illumination of the jungle in a wide path toward the landing field
made for weirdness in the look of things. There were arching giant
ferns and columnar trees which grew above them, and the
extraordinary lanceolate underbrush of the jungle. The flood lamps,
set level with the ground, lighted everything from below. The foliage,
then, was brightly lit against the black night-sky—brightly lit enough to
dim-out the stars. There were astonishing contrasts of light and
shadow everywhere.
"On ahead!" commanded Huyghens, waving. "Hup!"
He swung the bear-quarters door shut. He moved toward the landing
field through the lane of lighted forest. The two giant male Kodiaks
lumbered ahead. Sitka Pete dropped to all fours and prowled.
Sourdough Charley followed closely, swinging from side to side.
Huyghens came alertly behind the two of them, and Faro Nell brought
up the rear with Nugget following her closely.
It was an excellent military formation for progress through dangerous
jungle. Sourdough and Sitka were advance-guard and point,
respectively, while Faro Nell guarded the rear. With Nugget to look
after, she was especially alert against attack from behind. Huyghens
was, of course, the striking force. His gun fired explosive bullets
which would discourage even sphexes, and his night-sight—a cone of
light which went on when he took up the trigger-slack—told exactly
where they would strike. It was not a sportsmanlike weapon, but the
creatures of Loren Two were not sportsmanlike antagonists. The
night-walkers, for example—But night-walkers feared light. They
attacked only in a species of hysteria if it were too bright.
Huyghens moved toward the glare at the landing field. His mental
state was savage. The Kodius Company station on Loren Two was
completely illegal. It happened to be necessary, from one point of
view, but it was still illegal. The tinny voice on the space phone was
not convincing, in ignoring that illegality. But if a ship landed,
Huyghens could get back to the station before men could follow, and
he'd have the disposal safe turned on in time to protect those who'd
sent him here.
But he heard the faraway and high harsh roar of a landing-boat rocket
—not a ship's bellowing tubes—as he made his way through the
unreal-seeming brush. The roar grew louder as he pushed on, the
three big Kodiaks padding here and there, sniffing thoughtfully,
making a perfect defensive-offensive formation for the particular
conditions of this planet.
He reached the edge of the landing field, and it was blindingly bright,
with the customary divergent beams slanting skyward so a ship could
check its instrument landing by sight. Landing fields like this had been
standard, once upon a time. Nowadays all developed planets had
landing grids—monstrous structures which drew upon ionospheres
for power and lifted and drew down star ships with remarkable
gentleness and unlimited force. This sort of landing field would be
found where a survey-team was at work, or where some strictly
temporary investigation of ecology or bacteriology was under way, or
where a newly authorized colony had not yet been able to build its
landing grid. Of course it was unthinkable that anybody would attempt
a settlement in defiance of the law!
Already, as Huyghens reached the edge of the scorched open space,
the night-creatures had rushed to the light like moths on Earth. The
air was misty with crazily gyrating, tiny flying things. They were
innumerable and of every possible form and size, from the white
midges of the night and multi-winged flying worms to those revoltingly
naked-looking larger creatures which might have passed for plucked
flying monkeys if they had not been carnivorous and worse. The
flying things soared and whirred and danced and spun insanely in the
glare. They made peculiarly plaintive humming noises. They almost
formed a lamp-lit ceiling over the cleared space. They did hide the
stars. Staring upward, Huyghens could just barely make out the blue-
white flame of the space-boat's rocket through the fog of wings and
bodies.

The rocket-flame grew steadily in size. Once, apparently, it tilted to

adjust the boat's descending course. It went back to normal. A speck
of incandescence at first, it grew until it was like a great star, and then
a more-than-brilliant moon, and then it was a pitiless glaring eye.
Huyghens averted his gaze from it. Sitka Pete sat lumpily—more than
a ton of him—and blinked wisely at the dark jungle away from the
light. Sourdough ignored the deepening, increasing rocket roar. He
sniffed the air delicately. Faro Nell held Nugget firmly under one huge
paw and licked his head as if tidying him up to be seen by company.
Nugget wriggled.
The roar became that of ten thousand thunders. A warm breeze blew
outward from the landing field. The rocket boat hurled downward, and
its flame touched the mist of flying things, and they shriveled and
burned and were hot. Then there were churning clouds of dust
everywhere, and the center of the field blazed terribly,—and
something slid down a shaft of fire, and squeezed it flat, and sat on it,
—and the flame went out. The rocket boat sat there, resting on its tail
fins, pointing toward the stars from which it came.
There was a terrible silence after the tumult. Then, very faintly, the
noises of the night came again. There were sounds like those of
organ pipes, and very faint and apologetic noises like hiccups. All
these sounds increased, and suddenly Huyghens could hear quite
normally. Then a side-port opened with a quaint sort of clattering, and
something unfolded from where it had been inset into the hull of the
space boat, and there was a metal passageway across the flame-
heated space on which the boat stood.
A man came out of the port. He reached back in and shook hands
very formally. He climbed down the ladder rungs to the walkway. He
marched above the steaming baked area, carrying a traveling bag.
He reached the end of the walk and stepped gingerly to the ground.
He moved hastily to the edge of the clearing. He waved to the space
boat. There were ports. Perhaps someone returned the gesture. The
walkway folded briskly back up to the hull and vanished in it. A flame
exploded into being under the tail fins. There were fresh clouds of
monstrous, choking dust and a brightness like that of a sun. There
was noise past the possibility of endurance. Then the light rose swiftly
through the dust cloud, and sprang higher and climbed more swiftly
still. When Huyghens' ears again permitted him to hear anything,
there was only a diminishing mutter in the heavens and a small bright
speck of light ascending to the sky and swinging eastward as it rose
to intercept the ship which had let it descend.
The night noises of the jungle went on. Life on Loren Two did not
need to heed the doings of men. But there was a spot of
incandescence in the day-bright clearing, and a short, brisk man
looked puzzledly about him with a traveling bag in his hand.
Huyghens advanced toward him as the incandescence dimmed.
Sourdough and Sitka preceded him. Faro Nell trailed faithfully,
keeping a maternal eye on her offspring. The man in the clearing
stared at the parade they made. It would be upsetting, even after
preparation, to land at night on a strange planet, and to have the
ship's boat and all links with the rest of the cosmos depart, and then
to find one's self approached—it might seem stalked—by two
colossal male Kodiak bears, with a third bear and a cub behind them.
A single human figure in such company might seem irrelevant.

The new arrival gazed blankly. He moved, startledly. Then Huyghens

called:
"Hello, there! Don't worry about the bears! They're friends!"
Sitka reached the newcomer. He went warily down-wind from him and
sniffed. The smell was satisfactory. Man-smell. Sitka sat down with
the solid impact of more than a ton of bear-meat landing on packed
dirt. He regarded the man amiably. Sourdough said "Whoosh!" and
went on to sample the air beyond the clearing. Huyghens
approached. The newcomer wore the uniform of the Colonial Survey.
That was bad. It bore the insignia of a senior officer. Worse.

"Hah!" said the just-landed man. "Where are the robots? What in all
the nineteen hells are these creatures? Why did you shift your
station? I'm Roane, here to make a progress report on your colony."
Huyghens said:
"What colony?"
"Loren Two Robot Installation—" Then Roane said indignantly, "Don't
tell me that that idiot skipper dropped me at the wrong place! This is
Loren Two, isn't it? And this is the landing field. But where are your
robots? You should have the beginning of a grid up! What the devil's
happened here and what are these beasts?"
Huyghens grimaced.
"This," he said politely, "is an illegal, unlicensed settlement. I'm a
criminal. These beasts are my confederates. If you don't want to
associate with criminals you needn't, of course, but I doubt if you'll
live till morning unless you accept my hospitality while I think over
what to do about your landing. In reason, I ought to shoot you."
Faro Nell came to a halt behind Huyghens, which was her proper
post in all out-door movement. Nugget, however, saw a new human.
Nugget was a cub, and, therefore, friendly. He ambled forward
ingratiatingly. He was four feet high at the shoulders, on all fours. He
wriggled bashfully as he approached Roane. He sneezed, because
he was embarrassed.
His mother overtook him swiftly and cuffed him to one side. He
wailed. The wail of a six-hundred-pound Kodiak bear-cub is a
remarkable sound. Roane gave ground a pace.
"I think," he said carefully, "that we'd better talk things over. But if this
is an illegal colony, of course you're under arrest and anything you
say will be used against you."
Huyghens grimaced again.
"Right," he said. "But now if you'll walk close to me, we'll head back to
the station. I'd have Sourdough carry your bag—he likes to carry
things—but he may need his teeth. We've half a mile to travel." He
turned to the animals. "Let's go!" he said commandingly. "Back to the
station! Hup!"
Grunting, Sitka Pete arose and took up his duties as advanced point
of a combat team. Sourdough trailed, swinging widely to one side and
another. Huyghens and Roane moved together. Faro Nell and Nugget
brought up the rear. Which, of course, was the only relatively safe
way for anybody to travel on Loren Two, in the jungle, a good half
mile from one's fortress-like residence.
But there was only one incident on the way back. It was a night-
walker, made hysterical by the lane of light. It poured through the
underbrush, uttering cries like maniacal laughter.
Sourdough brought it down, a good ten yards from Huyghens. When
it was all over, Nugget bristled up to the dead creature, uttering cub-
growls. He feigned to attack it.
His mother whacked him soundly.

II
There were comfortable, settling-down noises below. The bears
grunted and rumbled, but ultimately were still. The glare from the
landing field was gone. The lighted lane through the jungle was dark
again. Huyghens ushered the man from the space boat up into his
living quarters. There was a rustling stir, and Semper took his head
from under his wing. He stared coldly at the two humans. He spread
monstrous, seven-foot wings and fluttered them. He opened his beak
and closed it with a snap.
"That's Semper," said Huyghens. "Semper Tyrannis. He's the rest of
the terrestrial population here. Not being a fly-by-night sort of
creature, he didn't come out to welcome you."
Roane blinked at the huge bird, perched on a three-inch-thick perch
set in the wall.
"An eagle?" he demanded. "Kodiak bears—mutated ones you say,
but still bears—and now an eagle? You've a very nice fighting unit in
the bears."
"They're pack animals, too," said Huyghens. "They can carry some
hundreds of pounds without losing too much combat efficiency. And
there's no problem of supply. They live off the jungle. Not sphexes,
though. Nothing will eat a sphex, even if it can kill one."
He brought out glasses and a bottle. He indicated a chair. Roane put
down his traveling bag. He took a glass.
"I'm curious," he observed. "Why Semper Tyrannis? I can understand
Sitka Pete and Sourdough Charley as names. The home of their
ancestors makes them fitting. But why Semper?"
"He was bred for hawking," said Huyghens. "You sic a dog on
something. You sic Semper Tyrannis. He's too big to ride on a
hawking glove, so the shoulders of my coats are padded to let him
ride there. He's a flying scout. I've trained him to notify us of sphexes,
and in flight he carries a tiny television camera. He's useful, but he
hasn't the brains of the bears."
Roane sat down and sipped at his glass.
"Interesting ... very interesting! But this is an illegal settlement. I'm a
Colonial Survey officer. My job is reporting on progress according to
plan, but nevertheless I have to arrest you. Didn't you say something
about shooting me?"
Huyghens said doggedly:
"I'm trying to think of a way out. Add up all the penalties for illegal
colonization and I'd be in a very bad fix if you got away and reported
this set-up. Shooting you would be logical."
"I see that," said Roane reasonably. "But since the point has come up
—I have a blaster trained on you from my pocket."
Huyghens shrugged.
"It's rather likely that my human confederates will be back here before
your friends. You'd be in a very tight fix if my friends came back and
found you more or less sitting on my corpse."
Roane nodded.
"That's true, too. Also it's probable that your fellow terrestrials
wouldn't co-operate with me as they have with you. You seem to have
the whip hand, even with my blaster trained on you. On the other
hand, you could have killed me quite easily after the boat left, when
I'd first landed. I'd have been quite unsuspicious. So you may not
really intend to murder me."
Huyghens shrugged again.
"So," said Roane, "since the secret of getting along with people is that
of postponing quarrels—suppose we postpone the question of who