3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.4.1 Lipophilicity versus hydrophilicity
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Written by Resident Doctor Committee · Published
Lipid and water preference
Lipophilicity and hydrophilicity describe a drug's relative preference for lipid or water, on a continuum.
LogP compares the un-ionised drug in octanol and water, and a logP of 3 means a 1,000-fold ratio.
Crossing membranes
Lipid-soluble drugs cross cell membranes and accumulate in adipose tissue.
Polar, ionised or water-soluble drugs cross lipid membranes poorly, including the blood-brain barrier, which shapes how they distribute and how they are eliminated.
Lipophilic and hydrophilic drugs compared
Feature | Lipophilic | Hydrophilic |
|---|---|---|
Distribution | Extensive tissue partitioning | Mostly limited to body water |
Elimination | Usually metabolised before excretion | Often excreted unchanged by the kidney |
Dialysis | Usually of little use | Can work if binding and volume of distribution are low |
Example | Benzodiazepines | Lithium, sulpiride, amisulpride |
Benzodiazepines are highly lipid soluble, so they cross the blood-brain barrier readily to reach gamma-aminobutyric acid type A (GABA-A) receptors. They are well absorbed orally, highly protein bound, metabolised in the liver and cross the placenta.
Repeated dosing builds tissue stores of a lipophilic drug and prolongs washout.
The balance for oral absorption
Passive membrane permeation and oral absorption need a balance of lipophilic and hydrophilic character. The drug must dissolve in the aqueous layer at the gut wall and then enter the lipid bilayer.
High lipophilicity can reduce dissolution and increase binding or metabolism.
High hydrophilicity limits passive entry through membranes.