Flashcards in Pharmacokinetics Biopharmaceutics (3/3) Deck (18):
What is the issue with an API having a small or negative logP?
The API is so water soluble that it is not easily able to pass through the fatty membranes of the GIT
What is the issue with an API having a large (and positive) logP?
The compound is so water insoluble that it is difficult for it to get into solution in order to approach the fatty membranes
What is the 'optimal' logP value for the purposes of oral absorption?
What is the pH partition hypothesis?
Assumed that only lipid soluble molecules are able to cross the GIT membranes
Most drugs are weak electrolytes (i.e. weak acids or bases)
It is expected that only the unionised form of a drug will cross the membrane - the ionised form will not cross
How is the pH partition hypothesis and the Hendelson-Haselbach equation linked?
The HH equation can be used to calculate the % of drug in the GIT that is ionised at the pH of the GIT
Why, at a low pH, are weak acid APIs often largely unionised?
The concentration of H+ in solution is high, so the acid groups of API cannot dissociate
Why, at a high pH, are weak acid APIs largely ionised?
The concentration of H+ is low, so the acid groups of the APIs can easily dissociate
Why, at a low pH, are weak base APIs largely ionised?
Concentration of H+ in solution is high so the basic groups of the basic APIs will take up the H+
Why, at a high pH, are weak base APIs largely unionised?
Concentration of H+ in solution is low, so there is no driving force pushing H+ onto the basic groups of the APIs
What state exists when pH = pKa?
The API is 50% ionised and 50% unionised
What is the rule of thumb linking pKa and ionisation?
You only need to go +/-2 units away from the pKa value to get almost complete ionisation or almost complete lack of ionisation
What should be noted about the unstirred water layer at the surface of the GIT membranes?
The pH and charge at the membrane surface is not necessarily the same as that in the bulk of the GIT
What is Lipinski's rule of 5?
Candidate drugs that conform to the "rule of 5" stand a better chance of progressing to market
Consists of 4 criteria that happen to feature numbers that are divisible by 5
List the 4 criteria of Lipinski's rule of 5
Molecule has fewer than 5 H-bond donors (e.g. -OH2, -NH2)
Molecule has fewer than 10 H-bond acceptors (e.g. the oxygen atom of -C=O or of -OH)
Molecule has a total MW of less than 500
Molecule has a logP value of less than 5
Define: The biopharmaceutics classification system (BCS)
Used to classify drugs based on their per,eability and solubility
When is a drug substance considered highly soluble?
When the highest dose strength is soluble in
When is a drug substance considered highly permeable?
When the extent of absorption in humans is determined to be >90% of an administered dose, in comparison to an intravenous reference dose