1
Partition and distribution coefficients
Absorption of drugs
There are a number of ways that drugs are absorbed,
1
but the most common route is passive
transport (diffusion). Passive transport does not require an input of energy.
A cell membrane has a central layer that is lipophilic (hydrophobic). The IUPAC definition of
lipophilic is:
‘Having an affinity for fat and high lipid solubility: a physicochemical property which describes a
partitioning equilibrium of solute molecules between water and an immiscible organic solvent,
favouring the latter, and which correlates with bioaccumulation.’
The relative solubility of a substance in water and an organic solvent (water-immiscible) is a
measure of lipophilicity.
Experiments have shown that lipophilicity is an important property of a drug that influences passive
transport across cell membranes. A drug molecule needs to be sufficiently lipophilic that it enters
the lipid core of a cell membrane, but not so lipophilic that it is held in that core and does not move
into the cell.
Partition coefficient
In drug discovery and development, lipophilicity is usually
expressed by the partition between water and octan-1-ol.
The partition coefficient, P, of a drug is given by
[ ]
[ ]
where
[drug]octan-1-ol = concentration of drug in octan-1-ol
[drug]water = concentration of drug in water
A sample of the drug is shaken with a mixture of octan-1-ol and
water and its concentration in each layer is determined.
It is usual to give the logP value (the logarithm to the base 10 of
the partition coefficient). Sometimes a value is calculated - from
knowledge of the molecular structure - rather that determined
experimentally. These values are denoted by using clogP.
The drug molecule must be unionised in aqueous solution.
Distribution coefficient
Most drugs, however, are weak acids or weak bases that partially ionise when dissolved in water.
2
HA = acid (the drug molecule); H2O = base
A− = conjugate base (the drug anion); H3O+ =
conjugate acid
B = base (the drug molecule); H2O = acid
OH− = conjugate base (the drug anion); BH+ =
conjugate acid
1
See Pharmacokinetic processes: absorption.
2
See Ionisation of drug molecules and Drugs and acid dissociation constants.
Figure1 The shake flask method.
Water
layer
Octan-1-ol
layer
Figure 2 Partition between
octan-1-ol and water.
[drug]octan-1-ol
[drug]water
