Lecture 13 - Optimising drug properties to ensure good oral bioavailability

Question 1

Requirements for a good drug

Answer 1

1. efficacy- must achieve the therapeutic effect and be an appropriate size and structure to interact with target
2. chemically stable for whole shelf life
3. soluble
4. Suitable LogP- 1-3
5. oral bioavailability
6. Favourable safety profile- not too many side effects.

Question 2

Fick’s first law of diffusion equation. Label it

Answer 2

Question 3

What does Fick’s diffusion equation describe/

Answer 3

1. drug diffusion across membrane
2. can also be applied to the diffusion rate across the whole epithelium

Question 4

The partition coefficient, P, tells us….? It is usually expressed as…

Answer 4

the lipophilicity of a drug
log value- LogP

Question 5

The partition coefficient, P, of a drug between octanol and water is a substitute for what value in Fick’s equation?

Answer 5

K, the partition coefficient of a drug into a biological membrane in the Fick’s law of diffusion equation.

Question 6

How can P be determined

Answer 6

• shake flask
• dividing solubility in oil by solubility in water

Question 7

Modern methods to find LogP- using computers. What are these logP values known as?

Answer 7

cLogP

Question 8

If a drug is too hydrophilic…

Answer 8

good solubility, poor partitioning into cell membrane

Question 9

If a drug is too lipophilic…

Answer 9

solubility is poor and so will struggle to partition back out of the membrane. Overly lipophilic also may cause it too accumulate into fatty acids.

Question 10

What is the best logP value?

Answer 10

Best LogP = 1-3. Intermediate solubility and intermediate permeability.

Question 11

A very low LogP of <1

Answer 11

high solubility but low permeability

Question 12

A very high LogP, >5

Answer 12

poor solubility, high permeability

Question 13

What factors affect logP and lipophilicity?

Answer 13

Chemical structure determines a drug’s hydrophilicity and lipophilicity- such as ionization and hydrogen bonding

Question 14

Ionization of a drug effects its…

Answer 14

lipophilicity and hydrophilicity

Question 15

pH changes throughout the GI tract affects how the drug is absorbed. What is the pH of the fasted stomach, fed stomach and small intestine?

Answer 15

• 1.4-2.1
• 5
• 6.5

Question 16

What is the solubility and lipophilicity of a charged/ionized drug?

Answer 16

If a drug is charged/ionized it will be more soluble than a drug that is not. But there will be reduced membrane permeability

Question 17

An unionized drug will have better…?

Answer 17

lipophilicity and membrane permeability.

Question 18

Why are strong acids and bases poorly absorbed?

Answer 18

easily ionized so they have reduced membrane permeability.

Question 19

Most drugs are WEAK acids and bases because…

Answer 19

they have better absorption

Question 20

Describe the partition hypothesis

Answer 20

• AH and B: Unionized drug = lipophilic- optimal membrane transport
• A- and BH+: Ionized drug= hydrophilic- Reduced membrane transport.
• Ionized drugs accumulate on the side of the membrane where pH favours ionization. The uncharged drug passes through the membrane more readily.

Question 21

Limitations of the partition hypothesis

Answer 21

Doesn’t take into account…
1. type of epithelium
2. surface area of absorption site (ionised drugs are absorbed just not much, so a higher SA will increase absorption)
3. active transport and facilitated diffusion of drugs- transport proteins
4. residence time of drug at the delivery site
5. charged drugs can form ion pairs with oppositely charged species- increases lipophilicity

Question 22

Based on the pH partition hypothesis will the absorption of ibuprofen (pKa= 4.43) be highest in the fasted stomach (pH 2) or small intestine (pH 6.5). Use the Henderson-Hasselbalch equation for weak acids. Explain the results.

Answer 22

The percentage of unionised ibuprofen- HA is highest in the stomach. Unionised = more absorbable. Therefore absorption should be highest in the stomach
Reality:
- solubility in stomach is low
- small intestine is adapted with its large SA to absorb ibuprofen even in the ionised form.

Question 23

What is the difference between LogP and LogD?

Answer 23

• LogP only takes into account the partitioning of non-ionized species.
• The distribution coefficient, aka, LogD gives a more realistic measure of lipophilicity by taking into account ionized and unionized species.

Question 24

A higher value of LogD=

Answer 24

drug is more lipophilic

Question 25

LogD is affected by…

Answer 25

pH

Question 26

In addition to pH what else effects lipophilicity?

Answer 26

hydrogen bonding

Question 27

What is de-solvation? If a drug has more hydrogen bond how can this reduce lipophilicity?

Answer 27

• De-solvation= hydrogen bonds- to water - must be broken before a drug in solution can enter the lipid membrane
• More hydrogen bonds= more hydrogen bonds must be broken before a drug in solution can enter the lipid plasma membrane.

Question 28

The number of hydrogen bond donors in a drug relates to…

Answer 28

the number of OH and NH

Question 29

The number of hydrogen bond acceptors in a drug refers to…

Answer 29

the number of O and N in the drug

Question 30

The more hydrogen bond donors and acceptors you have in a drug…

Answer 30

the more hydrogen bonds form, so absorption into lipid membrane worsens

Question 31

What is Lipinksi’s rule of 5?

Answer 31

Poor oral absorption is likely if two or more of the following criteria are broken….
1. The MW is less than/equal to 500 (size- increased MW, decreased flux)
2. LogP is less than/equal to 5
3. Number of hydrogen bond donors is less than/equal to five
4. Hydrogen bond acceptors is less than/equal to 10

Question 32

Some drugs break Lipinski’s rule of 5 but are still absorbed at acceptable levels. Give examples.

Answer 32

• Antibiotics, vitamins, cardiac glycosides and antifungals

Question 33

What are Verber’s rules?

Answer 33

Absorption is likely if…?
- The number of rotatable bonds to be less than/equal to 10. Bigger molecule= more rotatable bonds.
- Total polar surface area of less than/equal to 140A2 OR total H bond count of less than/ equal to12.

Question 34

We can modify drugs to increase bioavailability as long as it doesn’t affect the binding of a drug to its target. Give examples of these modifications.

Answer 34

• Incorporate ionizable groups to increase solubility
• Changing the pKa of functional groups to increase lipophilicity
• Reducing the number of hydrogen bond donors or acceptors
• Pro-drug strategies – drug is chemically modified with lipophilic groups. Once absorbed into cell, metabolic processes occur to remove the groups and release the drug
• Permeation enhancers- improve absorption of drugs by altering membrane fluidity, for example.
• Formulation modification and increasing residence time.
• Inhibition of efflux transporters (eg. P-glycoprotein)- kick drugs out of the membrane.

Question 35

Many medicines actually contain ………………. rather than the original APIs.

Answer 35

pro drugs.