Basic Pharmacokinetics By Sunil S.J

Table of Contents：

Preface                                            xiii
About the authors                                  xv
Introduction and overview                      1   (16)
  Use of drugs in disease states               1   (1)
  Important definitions and descriptions       2   (2)
  Sites of drug administration                 4   (2)
  Review of ADME processes                     6   (1)
  Pharmacokinetic models                       7   (5)
  Rate processes                               12  (5)
Mathematical review                            17  (12)
  Introduction                                 17  (1)
  A brief history of pharmacokinetics          17  (1)
  Hierarchy of algebraic operations            18  (1)
  Exponents and logarithms                     18  (1)
  Variables, constants and parameters          19  (2)
  Significant figures                          21  (1)
  Units and their manipulation                 21  (1)
  Slopes, rates and derivatives                21  (2)
  Time expressions                             23  (1)
  Construction of pharmacokinetic sketches     23  (6)
  (profiles)
Intravenous bolus administration               29  (24)
(one-compartment model)
  Introduction                                 29  (1)
  Useful pharmacokinetic parameters            30  (2)
  The apparent volume of distribution (V)      32  (4)
  The elimination half life (t1/2)             36  (2)
  The elimination rate constant (K or Kel)     38  (2)
  Plotting drug concentration versus time      40  (2)
  Intravenous bolus administration of          42  (1)
  drugs: summary
  Intravenous bolus administration:            42  (2)
  monitoring drug in urine
  Use of urinary excretion data                44  (9)
Clearance concepts                             53  (34)
  Introduction                                 53  (2)
  Clearance definitions                        55  (1)
  Clearance: rate and concentration            56  (1)
  Clearance: tank and faucet analogy           56  (2)
  Organ clearance                              58  (1)
  Physiological approach to clearance          59  (5)
  Estimation of systemic clearance             64  (1)
  Calculating renal clearance (Clr) and        64  (1)
  metabolic clearance (Clm)
  Determination of the area under the          65  (2)
  plasma concentration versus time curve:
  application of the trapezoidal rule
  Elimination mechanism                        67  (1)
  Use of creatinine clearance to determine     68  (19)
  renal function
    Problem set 1                              77  (10)
Drug absorption from the gastrointestinal      87  (10)
tract
  Gastrointestinal tract                       87  (2)
  Mechanism of drug absorption                 89  (3)
  Factors affecting passive drug absorption    92  (1)
  pH-partition theory of drug absorption       93  (4)
Extravascular routes of drug administration    97  (28)
  Introduction                                 97  (2)
  Drug remaining to be absorbed, or drug       99  (2)
  remaining at the site of administration
  Determination of elimination half life       101 (1)
  (t1/2) and elimination rate constant (K
  or Kel)
  Absorption rate constant (Ka)                102 (1)
  Lag time (T0)                                103 (1)
  Some important comments on the absorption    104 (1)
  rate constant
  The apparent volume of distribution (V)      105 (1)
  Time of maximum drug concentration, peak     105 (2)
  time (tmax)
  Maximum (peak) plasma concentration          107 (2)
  (Cp)max
  Some general comments                        109 (1)
  Example for extravascular route of drug      110 (4)
  administration
  Flip-flop kinetics                           114 (11)
    Problem set 2                              117 (8)
Bioavailability/bioequivalence                 125 (34)
  Introduction                                 125 (1)
  Important definitions                        126 (1)
  Types of bioavailability                     126 (3)
  Bioequivalence                               129 (1)
  Factors affecting bioavailability            130 (1)
  The first-pass effect (presystemic           130 (1)
  clearance)
  Determination of the area under the          131 (4)
  plasma concentration-time curve and the
  cumulative amount of drug eliminated in
  urine
  Methods and criteria for bioavailability     135 (8)
  testing
  Characterizing drug absorption from          143 (2)
  plasma concentration versus time and
  urinary data following the administration
  of a drug via different extravascular
  routes and/or dosage forms
  Equivalency terms                            145 (1)
  Food and Drug Administration codes           145 (2)
  Fallacies on bioequivalence                  147 (1)
  Evidence of generic bioinequivalence or      148 (11)
  of therapeutic inequivalence for certain
  formulations approved by the Food and
  Drug Administration
    Problem set 3                              149 (10)
Factors affecting drug absorption:             159 (12)
physicochemical factors
  Dissolution rate                             159 (1)
  Dissolution process                          159 (1)
  Noyes-Whitney equation and drug              160 (1)
  dissolution
  Factors affecting the dissolution rate       161 (10)
Gastrointestinal absorption: role of the       171 (14)
dosage form
  Introduction                                 171 (1)
  Solution (elixir, syrup and solution) as     172 (1)
  a dosage form
  Suspension as a dosage form                  172 (1)
  Capsule as a dosage form                     173 (1)
  Tablet as a dosage form                      173 (2)
  Dissolution methods                          175 (1)
  Formulation and processing factors           175 (3)
  Correlation of in vivo data with in vitro    178 (7)
  dissolution data
Continuous intravenous infusion                185 (36)
(one-compartment model)
  Introduction                                 185 (3)
  Monitoring drug in the body or blood         188 (1)
  (plasma/serum)
  Sampling drug in body or blood during        189 (14)
  infusion
  Sampling blood following cessation of        203 (1)
  infusion
  Use of post-infusion plasma concentration    204 (4)
  data to obtain half life, elimination
  rate constant and the apparent volume of
  distribution
  Rowland and Tozer method                     208 (13)
    Problem set 4                              211 (10)
Multiple dosing: intravenous bolus             221 (22)
administration
  Introduction                                 221 (4)
  Useful pharmacokinetic parameters in         225 (8)
  multiple dosing
  Designing or establishing the dosage         233 (1)
  regimen for a drug
  Concept of drug accumulation in the body     233 (3)
  (R)
  Determination of fluctuation (Φ):        236 (3)
  intravenous bolus administration
  Number of doses required to reach a          239 (1)
  fraction of the steady-state condition
  Calculation of loading and maintenance       239 (1)
  doses
  Maximum and minimum drug concentration at    240 (3)
  steady state
Multiple dosing: extravascular routes of       243 (26)
drug administration
  Introduction                                 243 (2)
  The peak time in multiple dosing to          245 (1)
  steady state (t'max)
  Maximum plasma concentration at steady       246 (1)
  state
  Minimum plasma concentration at steady       247 (1)
  state
  ``Average'' plasma concentration at          248 (1)
  steady state: extravascular route
  Determination of drug accumulation:          249 (1)
  extravascular route
  Calculation of fluctuation factor (Φ)    250 (1)
  for multiple extravascular dosing
  Number of doses required reaching a          251 (1)
  fraction of steady state: extravascular
  route
  Determination of loading and maintenance     252 (1)
  dose: extravascular route
  Interconversion between loading,             253 (16)
  maintenance, oral and intravenous bolus
  doses
    Problem set 5                              257 (12)
Two-compartment model                          269 (20)
  Introduction                                 269 (3)
  Intravenous bolus administration:            272 (4)
  two-compartment model
  Determination of the post-distribution       276 (1)
  rate constant (β) and the
  coefficient (B)
  Determination of the distribution rate       277 (1)
  constant (α) and the coefficient (A)
  Determination of micro rate constants:       278 (2)
  the inter-compartmental rate constants
  (k21 and K12) and the pure elimination
  rate constant (K10)
  Determination of volumes of distribution     280 (2)
  (V)
  How to obtain the area under the plasma      282 (1)
  concentration-time curve from time zero
  to time t and time
  General comments                             282 (1)
  Example                                      283 (3)
  Futher calculations to perform and           286 (3)
  determine the answers
    Problem set 6                              287 (2)
Multiple intermittent infusions                289 (12)
  Introduction                                 289 (2)
  Drug concentration guidelines                291 (1)
  Example: determination of a multiple         292 (1)
  intermittent infusion dosing regimen for
  an aminoglycoside antibiotic
  Dose to the patient from a multiple          293 (1)
  intermittent infusion
  Multiple intermittent infusion of a          294 (1)
  two-compartment drug: vancomycin ``peak''
  at 1 h post-infusion
  Vancomycin dosing regimen problem            295 (1)
  Adjustment for early or late drug            296 (5)
  concentrations
    Problem set 7                              299 (2)
Non-linear pharmacokinetics                    301 (18)
  Introduction                                 301 (3)
  Capacity-limited metabolism                  304 (1)
  Estimation of Michaelis-Menten parameters    305 (4)
  (Vmax and Km)
  Relationship between the area under the      309 (2)
  plasma concentration versus time curve
  and the administered dose
  Time to reach a given fraction of steady     311 (2)
  state
  Example: calculation of parameters for       313 (6)
  phenytoin
    Problem set 8                              317 (2)
Drug interactions                              319 (18)
  Introduction                                 319 (1)
  The effect of protein-binding interactions   320 (7)
  The effect of tissue-binding interactions    327 (1)
  Cytochrome P450-based drug interactions      328 (8)
  Drug interactions linked to transporters     336 (1)
Pharmacokinetic and pharmacodynamic            337 (8)
relationships
  Introduction                                 337 (1)
  Generation of a                              338 (4)
  pharmacokinetic-pharmacodynamic (PKPD)
  equation
  Pharmacokinetic and pharmacodynamic drug     342 (3)
  interactions
Pharmacokinetics and pharmacodynamics of       345 (16)
biotechnology drugs
  Introduction                                 345 (1)
  Proteins and peptides                        345 (6)
  Monoclonal antibodies                        351 (4)
  Oligonucleotides                             355 (1)
  Vaccines (immunotherapy)                     356 (1)
  Gene therapies                               357 (4)
Appendix: Statistical moment theory in           361 (16)
pharmacokinetics
  A.1 Introduction                             361 (1)
  A.2 Statistical moment theory                362 (12)
  A.3 Applications                             374 (3)
Glossary                                           377 (6)
References                                         383 (8)
Index                                              391

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