5. What makes a good drug

Question 1

What are some of the physiological barriers preventing a drug from its target? Assume the drug is taken orally

Answer 1

Stomach acid Digestive enzymes Metabolic activity Protein binding

Question 2

What is a critical property of a drug required for its function?

Answer 2

Solubility

Question 3

Where are p.o. drugs absorbed?

Answer 3

In the small intestine

Question 4

Describe permeability and log P

How can permeability be increased?

What is the ideal method for a drug to pass through intestinal cells?

Answer 4

log P = lipophilicity (too high and it won’t leave cellular bilayer, too low and it won’t partition into it)

Permeability: The velocity of molecule passage through a membrane barrier

Determinant of intestinal absorption and oral bioavailability

Increased by removing ionizable groups, increasing log P, and decreasing size/polarity

Ideally drugs are passively diffused which requires a golden window of log P values

Also active transport*, endo/transcytosis, and paracellular methods

*must be careful of efflux

Question 5

How does drug charge effect permeability? What is the net result of this for the drug crossing from an acidic to a basic environment?

How is the speed of permeability affected by the pH of the solution?

Answer 5

H-Acid is more permeable than Acid- + H+

Passive diffusion is enhanced in the direction of the higher pH (HA is sequestered as A- in alkaline environment)

Base + H+ is more permeable than H-Base+

Passive diffusion is inhanced in the opposite direction for bases (B is sequestered as HB+ in acidic environment)

Acidic drugs have a decreasing speed of permeability on a graph on increasing pH

Basic drugs have an increasing speed of permeability on a graph of increasing pH

Neutral drugs are unnafected by extracellular pH

Question 6

What are the two roles of active transporters? What property of drugs determines which of these roles it will experience?

Answer 6

Uptake (good for drugs) and Efflux (bad for drugs)

Bioavailability, metabolism, excretion, brain drug exposure etc. depend on active transporters

Structure

Ratios and affinities decide where the drug ends up

Question 7

What is one way to get Acyclovir triphosphate ( a polar drug that gets hydrolysed easily) into your cell?

Answer 7

Create a prodrug (or in this case a pro prodrug)

Valacyclovir is hydrolised and vontains a valine residue

Valine allows the pro prodrug to enter the cell, where it gets cleaved off (into acyclovir), where it is then phosphorylated by intracellular kinases

Question 8

What is P-glycoprotein and why is it a problem for drug design? When is it not a problem?

How can its effect be measured in vitro?

Answer 8

It is an efflux pump that targets hydrophobic molecules (mostly drugs) and shoots them out of the cell

Makes it very hard for drugs to stay in the cell if they need to be hydrophobic to function

(BUT eg an antihistamine that needs to affect the PNS but not the CNS makes use of P-gp to prevent it from crossing BBB)

“Hydrophobic vacuum cleaner”

Low resolution structure and flexible nature of protein make it hard to undertsand and therefore hard to inhibit

Look at drug efflux rate in basal-to-apical direction as well as apical-to-basal direction

Difference between two rates indicates active transport process

Question 9

Describe the process and phases of metabolism of xenobiotics

Answer 9

Phase I metabolism slightly increases drug polarity via hydroxylation/hydrolysis

Phase II metabolism increases polarity further via conjugation with glucuronic acid, sulfate, etc.

End result is liphophilic -> hydrophilic, allowing it to be soluble in water and therefore excreted

Very important in drug design, must be taken into account

Question 10

What enzyme family degrades most xenobiotics in the human body? What subfamily is most present in the GIT?

What is the graphefruit effect?

Answer 10

Cytochrome P450

Most common CYP3A subfamily (eg CYP3A4 in hepatocytes)

Grapefruit juice inhibits CYP3A in the enterocyte, the net result being an increase in the oral bioavailability of many drugs, which can cause problems

Question 11

What are some (8) structure modifications to improve Phase I stability? Phase II stability? (2)

Answer 11

Block metabolic site by adding fluorine/other blocking groups

Remove labile funcitonal group

Cyclization

Change ring size/chirality

Reduce lipophilicity

Replae unstable groups

Introduce electron-withdrawing groups or steric hindrance

Change phenolic hydroxyl to bioisostere group

Question 12

What are three mechanisms affecting drug concentrations in renal clearance?

Answer 12

Albumin (or other plasma protein)-bound proteins are retained and excreted less regularly

Limited number of active transporters in tubular secretion (blood -> collecting duct) which can be saturated (*FILTRATION IS INDEPENDED OF CONC)

Reabsorption occurs as well, and drugs are passively diffused here. Typically they are highly lipophilic or are acidic (sequestered out of acidic urine into neutral plasma)

Question 13

What are the three roles of transporters in liver hepatocytes?

What happens during enterohepatic cycling?

Answer 13

Hepatic uptake (blood -> hepatocyte)

Biliary clearance (hepatocyte -> bile canaliculus)

Hepatocyte efflux (hepatocyte -> blood)

Sometimes the drug is reabsorbed from the GI tract and returned to the systemic circulation. This causes a measurable increase in the plasma concentration of the drug, several half lives after the drug was administered, which delays its eventual disposition

Question 14

What are the Direct (4) and indirect (2) mechanisms that the microbiota affects drugs?

What happends as the drug decreases in concentration?

Where does this take place and what is a problem with the microbiome as a drug target?

Answer 14

Prodrug -> active metabolite

Active metabolite -> inactive metabolite

Drug -> toxic metabolite

Drug -> selective bacterial growth

Gut microbiota -> microbial metabolites

Host metabolites -> microbiota-modified host metabolites

Intestinal epithelal cells can efflux drugs back into the microbiota, and the liver excretes bile back into the microbiota as well

Mostly occurs in colon (bulk of bacteria present), as we all have different microbiomes this is subject to inter-patient variability

Question 15

What do the criteria for a “good drug” depend on?

Answer 15

The application of the drug:

Method of administration

The target

Required circulation time

Required dose

etc

Question 16

List Lipinski’s Rules of 5 and what that means for a compound

Answer 16

Compounds are more likely to have poor absorption/permeation when

• >5 H-bond donors (sum of OHs and NHs)
• MW > 500
• logP > 5
• >10 H-bond acceptors (Sum of all Ns and Os)
• Substrates for biological transporters are exceptions

Question 17

What is the leading challenge in drug development? How is it measured?

How can one molecule’s solubility change (wihtout any structural modification)? What happens if a drug is poorly soluble?

What structural properties affect solubility and what modifications are possible to increase solubility?

Answer 17

Solubility

Via the saturation shake-flask method (prepare a saturation soln and let it equilibrate, remove solid and quantify/analyze it)

By arranging in a crystaline structure, the material can become 1-100 times less soluble

To be dissolved, the drug must 1) be dissociated from is crystal structure, 2) a water molecule must be displaced as wel, 3) the drug molecule must replace the water in the hole, and 4) all of these steps must be energetically favorable

If a drug is poorly soluble, it will pass through your gut unabsorbed

Size, pKa, crystal lattice energy all determine solubility

Modifications include

Adding an ionizable group, reducing logP, add H bonding, reduce molecular weight, ot of plane substitutions to reduce packing, prodrug construction

Question 18

What are the 5 polymophic states and how are they different?

Answer 18

Amorphous: no shape

Polymorphs: nice lattice, stacking, just one molecule

Hydrate/solvate: stacking aided by water/solvent

Co-crystal: staking aided by a neutral coformer

Salt: Charged molecule stacked with the aid of counterion

Question 19

What is the tradeoff with solubility in terms of polymorphs?

Answer 19

Solubility is directly proportional to bioavailability but indirectly proportional to stability

Need to find the sweet spot for a drug to be soluble, bioavailable and stable enough

Question 20

What are some alternatives if a drug does not behave well from a solubility standpoint? What is the downside to this solution?

Answer 20

Formulation strategies (cosolvents, surfactants, cyclodextrins, solid dispersions, nanoparticles, liposomes, etc) can be developped

However, these add complexity and cost to the system

Some of these have their own problems (Surfactant-induced hypersensitivity after parenteral administration, immune reaction to nanoparticles, etc)

Question 21

What is the best first step when dealing with a “bad” drug?

How can this be applied when your drug is too polar?

What about when it’s too lipophilic?

Answer 21

Prodrugs

Inactive drugs that are modified once inside their target location to become active

Usually involve slapping on a “promoiety” to the intact drug (typically for access across barriers) which ar ethen cleaved off by intracellular enzymes

Most common example is bioconversion by esterases (molecules were too polar and had to be modified to partition across the cell wall

Solution: make an ester of the drug

When a drug is too lipophilic, moieties can be added to increase solubility that are then cleaved off by the body (typically involve salts?)

Another modification is to add groups that allow the drug to be recognised by peptide transporters

Question 22

What is a soft drug and when would you use it? What mechanisms allow their unique properties?

Answer 22

A soft drug is an active drug that is metabolised into its inactive state predictably and consistantly

This allows for controlled activity profiles, which is useful in anesthesia/anelgesia (among other uses)

Most techniques use esterases as they are highly conserved (moreso than CYPs)

Question 23

What are nucleic acid drugs and what are their drawbacks?

Answer 23

A type of biomolecular drug

Mostly antisence oligonucleotides or siRNA

Very large molecules, negatively charged, VERY sensitive to nuclease enzymes, but tremendous therapeutic potential

Largest hurdle in clinic is delivery

Question 24

What are the main drawbacks of protein drugs and how is it being dealt with?

Answer 24

Despite their potential uses, protein solubility, route of administration, distribution and stability are all factors that can hinder their application.

PEGylation address this issue by mimicking water, taking up space (so small molecules aren’t degraded by kidnesy, and increasing half life*

Antibodies are also useful in the context of autoimmune disease

* Conjugation to antibody Fc, albumin or PEGylation all increase half life