Lec 3 LOs

Question 1

what are the different modes of drug permeation into the body?

Answer 1

• intercellular junctions
• passive diffusion (lipid cell membranes)
• transporters
• endocytosis and exocytosis

Question 2

How can we order a series of drugs according to their efficiency in passive diffusion?

Answer 2

• ionizable groups cannot pass the membrane
• more lipophilic is better but not too much or too hydrophobic
• need the pH to be neutral because it will diffuse better

Question 2

what are the hydrophobic groups in a drug structure?

Answer 2

methyl
chloro
phenyl
hexyl
cyclohexyl

Question 3

what are the hydrophilic groups in a structure?

Answer 3

carboxylic acid
alcohol
amine
ketone
amide
ester

Question 4

What are the H-bond donors and acceptors in a drug structure?

Answer 4

Donors
OH
NH
Acceptors
O
N

Question 5

How can we predict the effect of a structural change in a drug on its solubility in water?

Answer 5

Lipinski’s rule of 5
- No more than 5 H-bond donors
- No more than 10 H-bond acceptors
- A molecular mass < 500
- A LogP that doesn’t exceed 5
– Like dissolves like
– More polar and ionizable groups along with H bonds
– Be lipophilic and hydrophilic

Question 6

Explain how logP values affect the ability of drugs to reach target sites.

Answer 6

• LogP < 0 ; favors water
• LogP = 0 ; equal
• LogP > 0 ; favors octanol (organic)
• Bigger LogP → more lipophilic
  – Typical values from -1 to 4
• If logP is > 5 than it will result in bad solubility, oral absorption, and increase metabolic turnover and can increase toxicity
• LogP helps to cross membrane barriers if in range and helps to determine the drug properties and if its effective

Question 7

Explain why the relationship of drug effectiveness vs. logP is parabolic.

Answer 7

• The optimal logP is the logP value corresponding to the max of the drug activity
• Lipophilicity improves drug permeation, but too much lipophilicity may hinder membrane crossing
  – Inc. or dec. based off of logPo

Question 8

How do you calculate ClogP of a drug molecule from the pi values of its groups?

Answer 8

Sum of all pi values

Question 9

How do you calculate the pi value of a constituent group from logP values of structurally related drugs?

Answer 9

Subtract from total to find ClogP

Question 10

How do we estimate logD using logP and pKa at a given pH?

Answer 10

LogD = LogP - (pH - pKa)