Drug Design 2 - Applied Bioinformatics Group

log P and log k
• Biological barriers are not simply lipid membranes
• Distribu%on across biological barriers can only be described
approximately by k 1 and k 2
• In most models of log k, log P is used to model permea%on
across biological membranes
• A simple bilinear model generally reproduces log k
reasonably well:
log P = log k 1 – log k 2
log k = a log P – b log (c P + 1) + d
a, b, c, d are constants that can be determined by
regression for the respec%ve biological barrier
log P and log k
• In experiments, one observes
more or less well-­‐defined
maxima for log P as a func%on of
log k
• Each barrier has an opDmal
lipophilicity, where log k is
maximal
• For this log P uptake across the
barrier is most effec%ve
• For lower and higher values of
log P, log k is reduced
• Good bioavailability thus
requires an average lipophilicity
of the compounds
Acid-­‐Base Equilibrium
• Many drugs are acids or bases
HA + H 2 O ® A -­‐ + H 3 O +
B + H 3 O + ® BH + + H 2 O
Gastric
absorption
Placental
barrier
Intestinal
absorption
Organic
membrane
• Their protona%on thus depends on the pH of the surrounding
medium
• Charged species (A -­‐ , BH + ) possess log P-­‐values that are about 3-­‐5
above the values of the corresponding neutral species
• Absorp%on of a drug thus dras%cally depends on the protona%on
state
• Bioavailability is consequently influenced by the pH of the
surrounding medium
BKK, p. 403