What makes a good drug? Desirable drug properties

Question 1

True/False? Structure-based drug design is linked to drug-like properties

Answer 1

False

However a lead compound must be optimized in tandem with structure-based research

Question 2

What is a necessary property of any drug-to-be?

Answer 2

It must be soluble

Question 3

What method of administration faces the most barriers before reaching the target tissue? Why is that method used anyway?

Answer 3

Oral administration

It is very convenient

Question 4

Where are drugs absorbed when they are taken orally?

Answer 4

In the microvili of the small intestine, via the blood vessels feeding to the portal vein

Question 5

What property determines intestinal absorption rate and oral bioavailability?

Answer 5

Permeability

Question 6

How are most drugs permeated through the intestines?

Answer 6

Passively

Question 7

How can permeability be increased?

Answer 7

Removing ionizable groups, increasing logP, and decreasing size and polarity

Question 8

Why is there a window of logP values instead of a cutoff for intestinal permeability?

Answer 8

The drug has to go from being in an aqueous environment to the lipid membrane, into the aqueous cytosol, back to the lipid membrane, then the aqueous bloodstream

Too High a logP and it won’t leave the bilayer
Too low and it won’t ever partition

Question 9

How does charge affect permeability?

Answer 9

Charge means lower logP, meaning less permeability

Acids and bases should be neutral to maximize their permeability

Question 10

Why do acidic drugs have a higher permeability than bases?

Answer 10

The neutral pH inside the cell will sequester the charged form of the drug making it very difficult for it to be effluxed (basic drugs stay neutral and establish an equilibrium across the membrane)

Question 11

What are the 5 main uses of active transporters?

Answer 11

Bioavailability
Excretion
Metabolism
Excretion
Brain drug exposure

Question 12

What kind of drug does PEPT1 transport?

Answer 12

Peptide-like drugs

Question 13

How can drugs interact to increase bioavailability?

Answer 13

By having one drug modify/compete with transporters for another drug

Question 14

What is an advantage of using a prodrug (or a proprodrug in the case of valacyclovir)?

Answer 14

Using an inactive form of a drug with moieties that allow for specific transport only to be modified into the functional version of the drug once inside the target tissue

Question 15

What is P-glycoprotein and what does it do?

Answer 15

Efflux pump

mediates ATP-dependent export of drugs from cells

Question 16

How can you measure Pgp efflux pump effect?

Answer 16

Grow epithelial monolayer on porous membrane

Load drugs on one side of layer, let equilibrate and measure conc on other side

Question 17

When is Pgp efflux desirable?

Answer 17

For tissue specificity

eg a drug that you want in the periphery but not in the brain

Question 18

What are the two phases of metabolism?

Answer 18

Phase I: oxidative or hydrolytic process like hydroxylation or ester hydrolysis
Phase II: enzyme-catalyzed conjugation with glucuronic acid, sulfate, etc

Question 19

What is first pass metabolism and how does grapefruit juice alter it?

Answer 19

The initial breakdown of most drugs takes place in the liver via CYP3A enzymes

Grapefruit juice inhibits these, increasing the amount of drug entering the bloodstream (can be good and bad)

Question 20

What are 4 of the 7 ways to Improve phase I metabolic stability?

Answer 20

Block metabolic sites by adding fluorine (or other blocking groups)
Remove labile functional groups
Cyclization
Change the ring size
Chance chirality
Reduce lipophilicity
Replace unstable groups

Question 21

What are the 2 ways to improve phase II metabolic stability?

Answer 21

Introduce electron-withdrawing groups or steric hindrance

Change in phenolic hydroxyl to bioisostere group

Question 22

Why do acidic drugs stay in the body longer than basic drugs?

Answer 22

The acidic urine favors the neutral drug, making it equilibrate with the cell plasma, whose pH of 7 sequesters its charged form

Question 23

What are the 5 direct mechanisms the microbiome can have on a drug?

Answer 23

Prodrug -> active metabolite
Active metaolite -> inactive metabolite
Drug -> microbial inhibition
Drug -> selective bacterial growth

Question 24

What are two indirect mechanisms the microbiome can affect the host?

Answer 24

Microbial metabolites

Microbiota-modified host metabolites

Question 25

What are the three ways the microbiome gets access to drugs?

Answer 25

Orally through the intestine
Intestinal efflux
Billiary excretion

Question 26

Where does gut microbiota metabolism occur?

Answer 26

In the colon (where most bacteria are)

Question 27

What do the criteria of a ‘good’ drug depend on? (4)

Answer 27

The method of administration
The target organ/tissue/cell type
The required circulation time
The required dose

Question 28

What are the Lipinski’s Rules of 5? What do they suggest?

Answer 28

Rules that were determined from studying drugs that failed and drugs that were readily bioavailable to see what each group had in common

It was determined that Poor absorption occurred more often when:
> 5 H-bond donors (count all OHs and NHs)
MW > 500
logP > 5
> 10 H-bond acceptors (count all Ns and Os)

The only exceptions are drugs that are substrates for biological transporters