Lecture 2: Membrane Permeability and Partitioning of Drugs Flashcards
What are the different modes of drug permeation into the body?
In order for drugs to be absorbed, they need to enter through a physical membrane like the GI tract, blood brain barrier and lipid membranes.
Most drugs are absorbed through membranes through passive diffusion.
Active transportation will bring in drug molecules that can’t passively diffuse. This method requires energy.
How would you order a series of drugs according to their efficacy in passive diffusion?
What are the hydrophobic and hydrophilic groups in a drug structure?
Hydrophobic:
Lipophilic and poorly solvated by water.
Normally non-polar hydrocarbons.
EXs: Methyl group, chloro, phenyl, hexyl, cyclohexyl.
Hydrophilic:
Lipophobic and readily solvated by water.
Normally polar and capable of H-bond formation.
EXs: alcohol, carboxylic acid, amine, ketone, amide and ester.
What are the hydrogen bond donors and acceptors in a drug structure?
Donors: Oxygen-Hydrogen and Nitrogen-Hydrogen bonds.
Acceptors: Nitrogen and Oxygen atoms.
How would you predict the effect of a structural change in a drug on its solubility in water?
The partition coefficient
How do logP values affect the ability of drugs to reach target sites?
LogP is a measure of lipophilicity (love of lipids)
Lipophilicity improve drug permeation but too much can hinder membrane crossing.
Larger LogP means the drug is more lipophilic (more hydrophobic).
Typical drugs have the LogP value for -1 to 4.
Why is the relationship of drug effectiveness vs. logP parabolic?
The optimal logP value corresponds to the maximum drug activity.
Lipophilicity improves drug permeation but too much may hinder membrane crossing and remain there instead.
Too much or too little will result in low drug effectiveness.
How do you calculate ClogP from the pi values of the constituent groups?
Using the logP of the compound, you will add all the pi values of the constituent groups.
How do you calculate the pi values of a constituent group from logP values of structural related drugs?
You can subtract the difference between the two structural related drugs.
How can you estimate logD using logP and pKa at a given pH?
LogD can be estimated based of the whether the drug is acidic or basic and what environment it is being placed in. The logD will be similar to logP if the drug is in a favorable, neutral environment. The logD will be less than logP at a higher or lower pH than the drug pka resulting in little to no absorption.
How can you predict the efficiency of passive diffusion of a drug with a known pKa at a given pH?
Using pka and pH can be used to determine what state of equilibrium the drug is in (ionized or nonionized) and using that information you can determine where the drug might be absorbed better.
Based off the drug’s pka value, where will it be absorbed in the body?
Drugs are best absorbed where the pH is neutral such as the jejunum which is between 5 and 7.
Acid drugs tend to be absorbed in the stomach where the pH is between 1 and 3.
Basic drugs would be best absorbed in the ileum with the pH between 6 and 8.
