What makes a good drug? Desirable drug properties Flashcards
True/False? Structure-based drug design is linked to drug-like properties
False
However a lead compound must be optimized in tandem with structure-based research
What is a necessary property of any drug-to-be?
It must be soluble
What method of administration faces the most barriers before reaching the target tissue? Why is that method used anyway?
Oral administration
It is very convenient
Where are drugs absorbed when they are taken orally?
In the microvili of the small intestine, via the blood vessels feeding to the portal vein
What property determines intestinal absorption rate and oral bioavailability?
Permeability
How are most drugs permeated through the intestines?
Passively
How can permeability be increased?
Removing ionizable groups, increasing logP, and decreasing size and polarity
Why is there a window of logP values instead of a cutoff for intestinal permeability?
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
How does charge affect permeability?
Charge means lower logP, meaning less permeability
Acids and bases should be neutral to maximize their permeability
Why do acidic drugs have a higher permeability than bases?
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)
What are the 5 main uses of active transporters?
Bioavailability Excretion Metabolism Excretion Brain drug exposure
What kind of drug does PEPT1 transport?
Peptide-like drugs
How can drugs interact to increase bioavailability?
By having one drug modify/compete with transporters for another drug
What is an advantage of using a prodrug (or a proprodrug in the case of valacyclovir)?
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
What is P-glycoprotein and what does it do?
Efflux pump
mediates ATP-dependent export of drugs from cells
How can you measure Pgp efflux pump effect?
Grow epithelial monolayer on porous membrane
Load drugs on one side of layer, let equilibrate and measure conc on other side
When is Pgp efflux desirable?
For tissue specificity
eg a drug that you want in the periphery but not in the brain
What are the two phases of metabolism?
Phase I: oxidative or hydrolytic process like hydroxylation or ester hydrolysis
Phase II: enzyme-catalyzed conjugation with glucuronic acid, sulfate, etc
What is first pass metabolism and how does grapefruit juice alter it?
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)
What are 4 of the 7 ways to Improve phase I metabolic stability?
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
What are the 2 ways to improve phase II metabolic stability?
Introduce electron-withdrawing groups or steric hindrance
Change in phenolic hydroxyl to bioisostere group
Why do acidic drugs stay in the body longer than basic drugs?
The acidic urine favors the neutral drug, making it equilibrate with the cell plasma, whose pH of 7 sequesters its charged form
What are the 5 direct mechanisms the microbiome can have on a drug?
Prodrug -> active metabolite
Active metaolite -> inactive metabolite
Drug -> microbial inhibition
Drug -> selective bacterial growth
What are two indirect mechanisms the microbiome can affect the host?
Microbial metabolites
Microbiota-modified host metabolites
