Lipid solubility
In order to cross cell membranes (to allow absorption and distribution), drugs must be lipid-soluble. Nitrogen and oxygen atoms within a drug structure impart polarity (uneven charge distribution), and this tends to make drugs less lipid-soluble. Therefore, drugs with multiple nitrogen and/or oxygen atoms in their structure may have some difficulty in crossing cell membranes.
Click here to view a short animation that demonstrates the impact of lipid solubility on the rate at which drugs can cross cell membranes.
A measure of the polarity of a drug’s structure which can predict how extensively drugs are absorbed and distributed is the topological polar surface area, or just polar surface area. This value, which has units of Ångströms2 (an Ångström is 0.1 nm) increases with the number of polar groups within the drug structure. It can be calculated for any drug via online java-based freeware, for example, this website, which requires Java to run.
Alternatively, lipid solubility of a drug may be determined experimentally, by measuring the degree to which a drug partitions from a water layer into an octanol layer in a beaker. The log10 of the octanol:water ratio is referred to as “logP”, with a logP of 1 indicating that the concentration of the drug in the octanol layer is 10× higher than in the water layer. LogP values for most drugs are greater than 1, and may be as high as 5.
Drugs are generally more lipid-soluble than they are water-soluble; it is not unusual for drugs to be between 10× and 1000× more lipid-soluble than water-soluble. The uncharged protonated form of a weak acid or the uncharged deprotonated form of a weak base are the lipid-soluble species within an equilibrium of ionised and unionised drug.
