Chemistry Reference
In-Depth Information
Lipoprotein
membrane
Gastrointestinal tract
Plasma
Unionised drug
Unionised drug
Ion
Ion
removed in bloodstream
Figure 2.5
A partition diagram of a cell membrane.
For any given drug (or, for that matter, for any biological membrane)
there must exist an optimal value of partition coefficient for transport of
drug across the membrane. This value is called
P
0
.
The situation becomes (even) more complicated if the drug ionises at
the pH of the body compartment. For weak acids and weak bases, the
aqueous and lipid solubility of the compound will depend on the extent to
which the drug is ionised, which in turn will depend on the p
K
a
of the acidic
and basic groups involved and the pH of the surroundings.
For weak acids that ionise as
H
A
HA
3
the unionised species, HA, will be much more lipid soluble, and will there-
fore cross biological membranes much more rapidly than will the anion A
.
This suggests that weak acids will be absorbed more efficiently across a
membrane when the pH of the surrounding solution is low and the weak
acid will be predominantly unionised. Such a situation is found in the
gastric juice of the stomach, which, due to the high concentration of
hydrochloric acid present, is at a pH of 1-2 (this is why gastric ulcers are so
painful: the hole in the stomach lining allows the acid to burn the under-
lying muscle layer). This theory is called the
pH partition hypothesis
, and
predicts that weakly acidic drugs such as aspirin, barbiturates, phenytoin,
etc. will be absorbed preferentially from the stomach rather than from the
more alkaline small intestine. In a region of high pH, the acidic drug will
ionise to give A
, which, since it is charged, will not diffuse well through a
hydrophobic lipid membrane.
For weak bases that ionise as
BH
OH
B
H
2
O
3
