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Pharmacokinetics and Metabolism in Drug Design 15 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)
ADME Absorption, distribution, metabolism and excretion
CNS Central nervous system
CYP2D6 Cytochrome P450 2D6 enzyme
GIT Gastrointestinal tract
PET Positive emission tomography
Average amount of drug in the body over a dosing interval Maximum amount of drug in the body over a dosing interval Minimum amount of drug in the body over a dosing interval Area under plasma concentration time curve Initial concentration after i. v. dose Average plasma concentration at steady state Free (unbound) plasma concentration Initial free (unbound) plasma concentration Steady state concentration Clearance Unbound clearance Hepatic clearance Intrinsic clearance Intrinsic clearance of unbound drug Oral clearance Plasma clearance Renal clearance Systemic clearance Dose
Extraction Fractional response Maximum response
A . -^min
16 2 Pharmacokinetics
F Fraction of dose reaching systemic circulation (bioavailability)
fu Fraction of drug unbound
KA Affinity constant
KB Dissociation constant for a competitive antagonist
Kd Dissociation constant
kel Elimination rate constant
Km Affinity constant (concentration at 50 % ymax)
ko Infusion rate
k+1 Receptor on rate
k-1 Receptor off rate
log D74 Distribution coefficient (octanol/buffer) at pH 7.4
ln2 Natural logarithm of 2 (i. e. 0.693)
pA2 Affinity of antagonist for a receptor (= - log10[KB])
Q Blood flow
RL Receptor ligand complex
RO Receptor occupancy
s Substrate concentration
t time after drug administration
T Dosing interval
t1/2 Elimination half-life
yd Volume of distribution
yd(f) Apparent volume of distribution of free (unbound) drug
ymax Maximum rate of reaction (Michaelis-Menten enzyme kinetics)
8 Dosing interval in terms of half-life (= T/t1/2)
Setting the Scene
Pharmacokinetics is the study of the time course of a drug within the body and incorporates the processes of absorption, distribution, metabolism and excretion (ADME). In general, pharmacokinetic parameters are derived from the measurement of drug concentrations in blood or plasma. The simplest pharmacokinetic concept is that based on total drug in plasma. However, drug molecules may be bound to a greater or lesser extent to the proteins present within the plasma, thus free drug levels may be vastly different from those of total drug levels. Blood or plasma are the traditionally sampled matrices due to (a) convenience and (b) to the fact that the concentrations in the circulation will be in some form of equilibrium with the tissues of the body. Because of analytical difficulties (separation, sensitivity) it is usually the total drug that is measured and used in pharmacokinetic evaluation. Such measurements and analysis are adequate for understanding a single drug in a single species in a number of different situations since both protein binding and the resultant unbound fraction are approximately constant under these conditions. When species or
2.2 Intravenous Administration: Volume of Distribution 117
drugs are compared, certain difficulties arise in the use of total drug and unbound (free) drug is a more useful measure (see below).
Intravenous Administration: Volume of Distribution
When a drug is administered intravenously into the circulation the compound undergoes distribution into tissues etc. and clearance. For a drug that undergoes rapid distribution a simple model can explain the three important pharmacokinetic terms: volume of distribution, clearance and half-life.
Volume of distribution (Vd) is a theoretical concept that connects the administered dose with the actual initial concentration (C0) present in the circulation. The relationship is shown below:
Vd = Dose/C0 (2.1)
For a drug that is confined solely to the circulation (blood volume is 80 mL kg-1) the volume of distribution will be 0.08 L kg-1. Distribution into total body water (800 mL kg-1) results in a volume of distribution of 0.8 L kg-1. Beyond these values the number has only a mathematical importance. For instance a volume of distribution of 2 L kg-1 means only, that less than 5 % of the drug is present in the circulation. The drug may be generally distributed to many tissues and organs or concentrated in only a few.