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Abstract
Absorption, distribution, metabolism, and excretion (ADME) prop-
erties such as absorption, clearance, and volume of distribution are
strongly influenced by physicochemical parameters. A lot of retro-
spective analyses have been performed to identify those attributes
that give rise to favorable ADME parameters. These attributes
should be incorporated in compound design to increase the chance
of identifying a compound with superior ADME properties.
Contents
9.1 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
9.2 Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
9.3 Molecular Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
9.4 pKa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
9.5 Lipophilicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
9.6 Topological Polar Surface Area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
9.7 Number of Hydrogen Bond Donors and Acceptors . . . . . . . . . . . 175
9.8 Number of (Aromatic) Rings and % SP3 Carbon Atoms . . . . . . 176
9.9 Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
9.10 Multiparameter Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Additional Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
9.1 ABBREVIATIONS
ADME Absorption, distribution, metabolism, and excretion
BCS Biopharmaceutics classification system
CNS Central nervous system
Data from Wenlock et al. (2003) and Leeson and Davis (2004).
clog P calculated lipophilicity when the compound is neutral; clog D7.4
calculated lipophilicity at a pH of 7.4; RB rotatable bond
Table 9.1 also highlights the fact that the average MW of oral
drugs steadily decreases going from phase I to the market. This
trend is also reflected in the number of HBDs and HBAs. (The same
trend also applies when going from hit to lead to candidate in drug
discovery.) However, the percentage of launched oral drugs that
has a MW <350 Da has steadily decreased from 6070% around
1985 to 3040% around 2005 (Leeson and Springthorpe 2007), and
there is a statistically significant difference between MW and the
number of HBAs and rotatable bonds (RBs) between drugs
launched before 1983 and between 1983 and 2002 (see Table 9.1).
Note that nonoral drugs have different physicochemical properties.
For example, injectable drugs have a higher number of HBDs,
HBAs, and RBs and a higher average MW, as well as a lower
mean clog P than oral drugs (Vieth et al. 2004).
Of course, ADME properties have to be balanced with other
properties such as potency, selectivity, toxicity, etc. Indeed, signi-
ficant differences exist in the average physicochemical properties
of drugs as a function of the type of target such as ion channels,
G protein-coupled receptors, proteases, kinases, etc. (Morphy
2006; Paolini et al. 2006). For some targets, such as those based
on the disruption of proteinprotein interaction, it is particularly
unlikely to stay within the rule of 5. In addition, the nature of the
bloodbrain barrier is such that cutoffs of certain physicochemical
parameters, such as MW, number of HBAs, and RBs, and topological
168 9 ADME PROPERTIES AND THEIR DEPENDENCE
Data from Leeson and Davis (2004) and Pajouhesh and Lenz (2005)
PSA polar surface area
Correlation coefficients (r) for a dataset of 1,719 marketed drugs are displayed in the lower diagonal and r values for a subset that
satisfies 1090% MW coverage (196563 Da) are displayed in the upper diagonal.
Data from Vieth et al. (2004)
ON number of oxygen and nitrogen atoms; OHNH number of OH and NH groups; total SA total surface area
*HBA is defined slightly different than ON, and HBD is defined slightly different than OHNH. See Vieth et al. (2004) for details.
9.2 BASIC CONCEPTS
169
170 9 ADME PROPERTIES AND THEIR DEPENDENCE
N N N N
N NH N NH
N N
N N
O O
HO HO
O OH
O O
O
Olmesartan medoxomil
O O
FIGURE 9.2. Structure N
of amiodarone.
I
O
Amiodarone
9.4 pKa
The degree of ionization of the drug is determined by the pH of the
medium (acidic in the stomach and upper intestine, but close to 7.4
systemically) and the pKa.
For acids:
AH H2 O $ A H3 O (9.2)
172 9 ADME PROPERTIES AND THEIR DEPENDENCE
pKa log A H3 O =AH (9.3)
For bases:
BH H2 O $ B H3 O (9.4)
pKa log B H3 O =BH (9.5)
For bases:
9.5 LIPOPHILICITY
Lipophilicity reflects the affinity of a drug molecule to be associated
with a nonpolar lipid-rich medium (in contrast to preferentially
residing in an aqueous medium). Lipophilicity is measured by
determining the partitioning between a buffered aqueous phase
and an organic phase, usually n-octanol, and is expressed as either
log P or log D. Log P reflects the partitioning when the compound is
neutral (i.e., not charged), whereas log D is measured at a specific
pH at which a fraction of the compound may be neutral and the rest
positively or negatively charged depending on the pH and the pKa.
logP log compoundorganic phase compoundaqueous phase (9.8)
logDpH log compoundorganic phase compoundaqueous phase
(9.9)
O N
Ebastine
Fa
F poor poor solubility;
FIGURE 9.5. permeability poor metabolic
Relationship between stability
lipophilicity and
bioavailability/fraction
absorbed.
0 5 logP
9.9 SOLUBILITY
Solubility is obviously of great importance for absorption of
oral drugs. However, this parameter still remains somewhat elu-
sive despite its apparent simplicity. Several aspects should be
considered.
25
20
15
10
5
0
0 2 4 6 8 10 12
pH
1 1
score
score
0 0
3 5 clogP 2 4 clogD
1 1
score
score
40 90
0 0
360 500 MW 20 120 TPSA
1 1
score
score
0 0
0.5 3.5 HBD 8 10 pKa
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9.10 MULTIPARAMETER OPTIMIZATION 181
Additional Reading
Kerns EH, Di L (2008) Drug-like properties: concepts, structure design and
methods: from ADME to toxicity optimization. Academic Press, Amster-
dam, The Netherlands
Mannhold R (2008) Molecular drug properties: measurement and predic-
tion. Wiley-VCH, Weinheim, Germany
Van De Waterbeemd H, Testa B (2008) Drug bioavailability: estimation of
solubility, permeability, absorption and bioavailability, 2nd edn. Wiley
VCH, Weinhein, Germany