Drug Design

Question 1

What are the differences between Log P and Log D?

Answer 1

1. Log P takes into account neutral drugs and doesn’t account for pH or ionization state. It is a constant value
2. Log D accounts for ionization state of the drug and measures lipophilicity

Question 2

True or False: For non-ionizable compounds, log D = log P at any pH

Answer 2

True

Question 3

Dissolution is often the rate limiting step due to what 3 parameters?

Answer 3

1. Solubility of drug particle size and surface area
2. Crystalline vs. salt drug formulation
3. Rate of disintegration

Question 4

What are the 5 key points of the pH-Partition Hypothesis on Drug Absorption

Answer 4

1. The GI and other membranes act like lipid barriers
2. The unionized form of the acidic of basic drug is preferentially absorbed
3. Most drugs are absorbed by passive diffusion
4. The rate of drug absorption and amount of drug absorbed are related to its oil-water partition coefficient (i.e. the more lipophilic the drug, the faster is its absorption)
5. Weak acidic and neutral drugs may be absorbed from the stomach, but basic drugs are not

Question 5

pKa of Chlordiazepoxide HCl

Answer 5

4.5

Question 6

pKa of Ketokonazole

Answer 6

6.4 due to N ring

Question 7

What are the 7 barriers in the human body that limit drug development?

Answer 7

i. Poor Absorption/distribution: GI tract, BBB, percutaneous, eye
ii. Poor aqueous solubility
iii. First-pass metabolism
iv. Toxicity (e.g. GI irritation)
v. Compliance issues, dosing frequency (sustained release/depot form)
vi. Poor patient acceptance (Taste, odor)
vii. Unstable, drug degrades on storage

Question 8

What functional groups are used in Carrier-linked Prodrugs?

Answer 8

1. –COOH
2. –SH
3. –OH
4. –PO(OH)2
5. –NH
6. –C=_O

Question 9

What is P?

Answer 9

Partition coefficient - the ratio of concentrations of unionized species dissolved in two immiscible solvents at equilibrium. P is constant

Question 10

What is D?

Answer 10

Distribution coefficient - ratio of all species dissolved in two immiscible solvents which are in equilibrium. D is pH dependent

Question 11

What intermediate is super important for prilosec that ultimately shuts down the H+ pump?

Answer 11

Sulphenamide intermediate

Question 12

4 Characteristics of Chemotherapy Prodrugs

Answer 12

1. Improves tumor site selectivity
2. Uses enzymes or proteins specifically upregulated in tumors to activate cytotoxicity in tumors
3. Can significantly reduce non-specific toxicity to normal cells
4. Reduce harsh side effects