The effect of solubility on drug action is, however, usually a question of equilibration
of the drug between the aqueous phase and the lipid phase of the cell membrane. This
leads us to a discussion of partition coefficients.
1.2.3 Partition Coefficients of Drug MoleculesThe partition coefficient of a drug is defined as the equilibrium constant
of drug concentrations (symbolized by the square brackets) in the two phases. Since
partition coefficients are difficult to measure in living systems, they are usually deter-
minedin vitro, using n-octanol as a model of the lipid phase and an aqueous phosphate
buffer at pH 7.4 as a model of the water phase. This permits standardized measurements
of partition coefficients. Because it is a ratio,Pis dimensionless. Pis also an additive
property of a molecule, since each functional group helps determine the polarity and
therefore the lipophilic or hydrophilic character of the molecule. These substituent con-
tributions are widely utilized in quantitative structure-activity studies, as discussed in
chapter 3, section 3.3.2.
Partition coefficients thoroughly influence drug transport characteristics during the
pharmacokinetic phase; that is, partition coefficients affect the way drugs reach the site of
action from the site of administration (e.g., injection site, gastrointestinal tract). Drugs
are usually distributed by the blood, but must also penetrate and traverse many barriers
before reaching the site of action. Hence, the partition coefficient (which reflects
a drug’s ability to be soluble in both aqueous and lipid phases) will determine what
tissues a given compound can reach. On the one hand, extremely water-soluble drugs
may be unable to cross lipid barriers (e.g., the blood–brain barrier) and gain access to
organs rich in lipids, such as the brain and other neuronal tissues. On the other hand,
compounds that are very lipophilic will be trapped in the first lipid environment they
encounter, like fat tissue, and will be unable to leave this site quickly to reach their
target. Naturally, the partition coefficient is only one of several physicochemical para-
meters that influence drug transport and diffusion, which itself is only one aspect
of drug activity. (The blood–brain barrier and its role will be discussed in detail in
section 3.4.2.1.)
The partition coefficient and concepts derived from it are particularly important in
explaining the mode of action of neurological drugs, such as anticonvulsants (chapter 8,
section 8.1.5) and general anesthetics, which must penetrate the blood–brain barrier
prior to exerting their biological effect.
1.2.3.1 The Overton Hypothesis of Anesthetic Activity
Anesthesia refers to the complete lack of somatic sensation; it involves the temporary
cessation of awareness, both of the surrounding environment and of the inner environ-
ment (“self”). Overton, at the turn of the last century, attempted to explain drug-induced
anesthesia through the following hypotheses:
28 MEDICINAL CHEMISTRY
P=[drug]lipid/[drug]water (1.2)