Drug Design 2 - Applied Bioinformatics Group

Experimental QuanDDes
• An important pharmacokine%c property is the
distribuDon coefficient n-­‐octanol/water P:
P = k 1/k 2
where k 1 and k 2 are rate constants for the transi%on
between phases (H 2 O ! octanol and vice versa).
P is typically given as its logarithm, log P.
• log P is important, as it describes a drug’s ability
to cross a lipophilic membrane (lipophilicity of n-­‐
octanol is similar to that of biological membranes)
DeterminaDon of log P
• log P is a measure of lipophilicity of a
compound
• log P can be determined by measuring
the change of concentraDon in a
three-­‐phase system H 2 O/octanol/H 2 O
• Compound is ini%ally dissolved in
water (A) and distributes over the
octanol phase (B) into the second
water phase (C)
• In equilibrium, concentra%ons of the
compound are constant in all three
phases
log P and log k
• log k is the logarithm of the rate
constants for crossing the membrane
• Crossing the membrane can be seen as
a two-­‐step mechanism:
1. water (inside) ! membrane
2. membrane ! water (outside)
• Obviously, this process can also be
described in terms of rate constants k 1
and k 2 :
log k = log k 1 + log k 2 + const.
k
k 1
H 2 O
octanol
H 2O
k 1
k 2
membrane
k 2
H 2O
BKK, p. 401
k 2
k 1