Physicochemical properties and drug action 3

partition coefficient

relative lipid/water distribution of a drug in its nonionized state

logP = [drug in octanol]/[drug in water]

pi value

component of calculating clogP

(+) value: substituent contributes more to lipid solubility than water solubility

(-) value: substituent contributes more to water solubility than to lipid solubility

log P < +0.5

water soluble

log P > +0.5

water insoluble

Water solubility: pros and cons

low absorption

low brain penetration

high clearance by the kidney due to polarity

lipid solubility: pros and cons

low absorption

poor dissolution (low bioavailability)

good permeability

high metabolic (liver) clearance

Lipinsky’s rule of 5

compounds are likely to have poor oral absorption when:

- MW > 500

- calc LogP > 5

- # H-bond donors > 5 (OH and NH groups)

- # H-bond acceptors >10 (Os and Ns)

increasing molecular weight of a compound leads to

lower permeability

lower solubility

increased # of metabolizable moieties

toxic pharmacophores

beyond the rule of 5s

rotatable bonds

- good bioavailability wants </= 10 RotB

TPSA

- good bioavailability wants </=140 A

Rule of 4

characteristics of drugs more likely to pass into the CNS (not P-gp substrates)

- MW < 400

- total N and O atoms </= 4

- basic pKa < 8

- TPSA </= 60 (additional guideline)