Preface xiii
About the authors xv
1 Introduction and overview 1
1.1 Use of drugs in disease states 1
1.2 Important definitions and descriptions 2
1.3 Sites of drug administration 4
1.4 Review of ADME processes 6
1.5 Pharmacokinetic models 7
1.6 Rate processes 12
2 Mathematical review 17
2.1 Introduction 17
2.2 A brief history of pharmacokinetics 17
2.3 Hierarchy of algebraic operations 18
2.4 Exponents and logarithms 18
2.5 Variables, constants and parameters 19
2.6 Significant figures 21
2.7 Units and their manipulation 21
2.8 Slopes, rates and derivatives 21
2.9 Time expressions 23
2.10 Construction of pharmacokinetic sketches (profiles) 23
3 Intravenous bolus administration (one-compartment model) 29
3.1 Introduction 29
3.2 Useful pharmacokinetic parameters 30
3.3 The apparent volume of distribution (V) 32
3.4 The elimination half life (t1/2) 36
3.5 The elimination rate constant (K or Kel) 38
3.6 Plotting drug concentration versus time 40
3.7 Intravenous bolus administration of drugs: summary 42
3.8 Intravenous bolus administration: monitoring drug in urine 42
3.9 Use of urinary excretion data 44
4 Clearance concepts 53
4.1 Introduction 53
4.2 Clearance definitions 55
4.3 Clearance: rate and concentration 56
4.4 Clearance: tank and faucet analogy 56
4.5 Organ clearance 58
4.6 Physiological approach to clearance 59
4.7 Estimation of systemic clearance 64
4.8 Calculating renal clearance (Clr) and metabolic
clearance (Clm) 64
4.9 Determination of the area under the plasma concentration
versus time curve: application of the trapezoidal rule 65
4.10 Elimination mechanism 67
4.11 Use of creatinine clearance to determine renal function 68
Problem set 1 77
5 Drug absorption from the gastrointestinal tract 87
5.1 Gastrointestinal tract 87
5.2 Mechanism of drug absorption 89
5.3 Factors affecting passive drug absorption 92
5.4 pH–partition theory of drug absorption 93
6 Extravascular routes of drug administration 97
6.1 Introduction 97
6.2 Drug remaining to be absorbed, or drug remaining
at the site of administration 99
6.3 Determination of elimination half life (t1/2) and
elimination rate constant (K or Kel) 101
6.4 Absorption rate constant (Ka) 102
6.5 Lag time (t0) 103
6.6 Some important comments on the absorption rate constant 104
6.7 The apparent volume of distribution (V) 105
6.8 Time of maximum drug concentration, peak time (tmax) 105
6.9 Maximum (peak) plasma concentration (Cp)max 107
6.10 Some general comments 109
6.11 Example for extravascular route of drug administration 110
6.12 Flip-flop kinetics 114
Problem set 2 117
7 Bioavailability/bioequivalence 125
7.1 Introduction 125
7.2 Important definitions 126
7.3 Types of bioavailability 126
7.4 Bioequivalence 129
7.5 Factors affecting bioavailability 130
7.6 The first-pass effect (presystemic clearance) 130
7.7 Determination of the area under the plasma concentration–time
curve and the cumulative amount of drug eliminated in urine 131
7.8 Methods and criteria for bioavailability testing 135
7.9 Characterizing drug absorption from plasma concentration
versus time and urinary data following the administration of
a drug via different extravascular routes and/or dosage forms 143
7.10 Equivalency terms 145
7.11 Food and Drug Administration codes 145
7.12 Fallacies on bioequivalence 147
7.13 Evidence of generic bioinequivalence or of therapeutic
inequivalence for certain formulations approved
by the Food and Drug Administration 148
Problem set 3 149
8 Factors affecting drug absorption: physicochemical factors 159
8.1 Dissolution rate 159
8.2 Dissolution process 159
8.3 Noyes–Whitney equation and drug dissolution 160
8.4 Factors affecting the dissolution rate 161
9 Gastrointestinal absorption: role of the dosage form 171
9.1 Introduction 171
9.2 Solution (elixir, syrup and solution) as a dosage form 172
9.3 Suspension as a dosage form 172
9.4 Capsule as a dosage form 173
9.5 Tablet as a dosage form 173
9.6 Dissolution methods 175
9.7 Formulation and processing factors 175
9.8 Correlation of in vivo data with in vitro dissolution data 178
10 Continuous intravenous infusion (one-compartment model) 185
10.1 Introduction 185
10.2 Monitoring drug in the body or blood (plasma/serum) 188
10.3 Sampling drug in body or blood during infusion 189
10.4 Sampling blood following cessation of infusion 203
10.5 Use of post-infusion plasma concentration data to
obtain half life, elimination rate constant and the
apparent volume of distribution 204
10.6 Rowland and Tozer method 208
Problem set 4 211
11 Multiple dosing: intravenous bolus administration 221
11.1 Introduction 221
11.2 Useful pharmacokinetic parameters in multiple dosing 225
11.3 Designing or establishing the dosage regimen for a drug 233
11.4 Concept of drug accumulation in the body (R) 233
11.5 Determination of fluctuation (F): intravenous
bolus administration 236
11.6 Number of doses required to reach a fraction of the
steady-state condition 239
11.7 Calculation of loading and maintenance doses 239
11.8 Maximum and minimum drug concentration at steady state 240
12 Multiple dosing: extravascular routes of drug administration 243
12.1 Introduction 243
12.2 The peak time in multiple dosing to steady state (t0
max) 245
12.3 Maximum plasma concentration at steady state 246
12.4 Minimum plasma concentration at steady state 247
12.5 ‘‘Average’’ plasma concentration at steady state:
extravascular route 248
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