5. What makes a good drug Flashcards
What are some of the physiological barriers preventing a drug from its target? Assume the drug is taken orally
Stomach acid Digestive enzymes Metabolic activity Protein binding
What is a critical property of a drug required for its function?
Solubility
Where are p.o. drugs absorbed?
In the small intestine
Describe permeability and log P
How can permeability be increased?
What is the ideal method for a drug to pass through intestinal cells?
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
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?
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
What are the two roles of active transporters? What property of drugs determines which of these roles it will experience?
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
What is one way to get Acyclovir triphosphate ( a polar drug that gets hydrolysed easily) into your cell?
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
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?
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
Describe the process and phases of metabolism of xenobiotics
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
What enzyme family degrades most xenobiotics in the human body? What subfamily is most present in the GIT?
What is the graphefruit effect?
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
What are some (8) structure modifications to improve Phase I stability? Phase II stability? (2)
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
What are three mechanisms affecting drug concentrations in renal clearance?
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)
What are the three roles of transporters in liver hepatocytes?
What happens during enterohepatic cycling?
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
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?
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
What do the criteria for a “good drug” depend on?
The application of the drug:
Method of administration
The target
Required circulation time
Required dose
etc
List Lipinski’s Rules of 5 and what that means for a compound
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
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?
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
What are the 5 polymophic states and how are they different?
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
What is the tradeoff with solubility in terms of polymorphs?
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
What are some alternatives if a drug does not behave well from a solubility standpoint? What is the downside to this solution?
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)
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?
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
What is a soft drug and when would you use it? What mechanisms allow their unique properties?
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)
What are nucleic acid drugs and what are their drawbacks?
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
What are the main drawbacks of protein drugs and how is it being dealt with?
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
