phrm 82400: exam 1: lecture 3: membrane permeability and partitioning of drugs

what are the characteristics of hydrophilic groups?

- lipophilic

- readily solvated by water ('water loving')

- typically polar and capable of H-bond formation

what are some examples of hydrophilic groups?

- alcohol

- carboxylic acid

- amine

- ketone

- amide

- ester

what are the characteristics of hydrophobic groups?

- lipophilic

- poorly solvated by water ('water hating')

= typically non-polar hydrocarbons

what are some examples of hydrophobic groups?

- methyl

- chloro

- phenyl

- hexyl

- cyclohexyl

what is the lipinski's rule of five?

a rule of thumb to describe druglikeness

- orally active drugs

what are the components of the lipinski's rule of five?

- no more than 5 H-bond donors (-OH, -NH)

- no more than 10 H-bond acceptors (O, N)

- a molecular mass less than 500

- a logP that does not exceed 5

what is the lipinski's rule of five based on?

the observation that orally active drugs are relatively small and moderately lipophilic

what is the equation for log10 value of a partition coefficient (P)?

P = [drug]org / [drug]aq

if logP > 0,

the drug favors water

if logP = 0,

equal distribution

if logP < 0,

the drug favors organic solution

what is the measure of lipophilicity?

bigger logP 0> more lipophilic (more hydrophobic)

typically drugs have logP values from __________

-1 to 4

hotseat: the logP value of drug A is 2. what is the ratio of the concentration of the drug in the organic phase to that in the aqueous phase?

a. 100:1

b. 2:1

c. 1:2

d. 1:100

a. 100:1

what is the relationship between in vivo drug activity and logP often described with?

parabola curve

what is optimal logP?

logP0 - logP value corresponding to the maximum of the drug activity

lipophilicity improves drug permeation, but too much lipophilicity may __________

hinder membrane crossing

the contributions of structural fragments to the molecule's logP are __________

additive

what is calculated logP (ClogP)?

sum of pi values of the fragments + logP

acidic drugs and basic drugs may exist in both __________ in the aqeuous phase

ionic and neutral forms

only the drug in its neutral form is (insoluble or soluble) in the organic phase

soluble

how is the partitioning of drug dependent on pH?

increase in ionization will lead to the accumulation of the drug in the aqueous phase

for partitioning of acidic and basic drugs, __________ is more informative than partition coefficient (P)

distribution coefficient (D)

- "effective logP"

at higher pH, logD is much less than the actual pH, which means...

the drug may not cross the lipid membrane well

what is the equation for logD when pH >> pKa?

logP - (pH - pKa)

at lower pH, logD is much less than the actual logP, which means...

the drug may not cross the lipid membrane well

what is the equation for logD when pH << pKa?

logP - (pKa - pH)