Unit 3 - Pro drugs 1 Flashcards
What is a prodrug?
Biologically inert derivatives of drug molecules that undergo an enzymatic and/or chemical conversion in vivo (within the living) to release the pharmacologically active parent drug
- a prodrug in itself lacks pharmacological activity
- upon bioconversion it becomes pharmacologically active
What are the advantages of prodrugs?
Improved tissue penetration - altered lipophilicity and/or solubility Reduced first pass metabolism - improves bioavailability Selective transformations of prodrug in target tissue may reduce/remove unwanted systemic effects of drug - avoids uptake in other tissues Altered pharmacokinetics - altered duration of action Improved pharmaceutics - reduced GI irritation - improved taste
What are the disadvantages of prodrugs?
More complex
- more to worry about
Possible chemical instability/storage problems
Interspecies variability of mechanism
- different enzymes expressed differently
Possible extra toxicity of prodrug moiety
Extra production costs
- more expensive
Give disadvantages of pro drugs
More complex
- more to worry about
Possible chemical instability/storage problems
Interspecies variability of mechanism
- different enzymes expressed differently
Possible extra toxicity of prodrug moiety
Extra production costs
- more expensive
What is the rate of passive diffusion governed by?
The concentration gradient across the membrane
- higher gradient = faster diffusion
The partition coefficient, P, for the drug between the lipid phase of the cell membrane and the aqueous phases either side
Increasing molecular size also affects membrane penetration
- rare for current drug molecules
Why don’t polar compounds easily cross cell membranes by passive diffusion?
Lipid bilayer does not allow polar molecules to diffuse
What is lipophilicity?
Lipophilicity refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene.
Preference for a drug molecule to dissolve in the lipid phase of the cell membrane rather than aqueous phase
What is lipophilicity?
Lipophilicity refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene.
Preference for a drug molecule to dissolve in the lipid phase of the cell membrane rather than aqueous phase
What is lipophilicity determined by?
Structural components of the molecule
- polar groups reduce lipophilicity
Give examples of polar groups that are commonly found in drugs to give rise to low lipophilicity
Acids Alcohols Amides - peptide Esters Charged groups
Give examples of non polar groups that are commonly found in drugs to give rise to high lipophilicity
Alkyl groups Aryl groups - rings Halogens Ethers
How is LogP measured?
A drug sample is partitioned between layers of octanol and water
- the concentration of sample in each layer is measured
Lipophilicity, P = concentration in organic [octanol] layer / concentration in aqueous layer.
Often, lipophilicity is presented as a log value [log10P]
e.g. If conc. octanol = 10, and conc. water =1 [relative units] P = 10, and Log P = 1.
How is lipophilicity presented?
A log value, Log10P
Why is octanol not a perfect model for a cell membrane?
For some CNS-acting drugs, where access may be especially difficult, combined figures for octanol/water and cyclohexane/water may be more reliable
- Blood Brain Barrier
Why does pH affect the lipophilicity of a drug?
If a drug molecule may be protonated at or near physiological pH its lipophilicity will vary greatly with the pH measurement
The ionised form of a drug will have a much lower P than the unionised form
- use buffer of physiological pH in place of water
- pH 7.4
