Prodrugs/Permeability

• What type of process is dissolution ?

  equilibrium - some of the drug will dissolved and some of the drug will precipitate back into the solid form
• what is the pka of highly passively permeable compounds ?

  between 4 and 11
• what happens to the permeability of a compounds pka goes below 4 or above 11 ? (pka of 4 would be an acid and 11 would be a base)

  the acid or base is so highly ionised, that the concentration of neutral form of the drug is too low to permeate the membrane
• why is ionisation of drugs important ?

  ionisation improves drug dissolution and solubility

  protein binding sites have evolved to bind ionised molecules
• what is the bioavailability like for lipophilic drugs that are very unionised in the GI tract ?

  low solubility therefore low absorption from GI tract
• what is the permeability like for very polar drugs with a log p of less than 1 and is too low ?

  low permeability as they do not want to permeate membranes which then limits their absorption
• what is the permeability like for very lipophilic drugs where log p is too high ?

  low permeability as they are poorly soluble
• why do very lipophilic drugs have poor bioavailability ?

  not very soluble and if they do get absorbed they are most likely to be metabolised by CYP450 enzymes in the liver
• what is the permeability, solubility and metabolism like for compounds with low lipophilicity (,<1) and are unionised ?

  low metabolism

  medium solubility

  low permeability due to low log p
• what is the permeability, solubility and metabolism like for compounds with moderate ionisation (pka 3-12) and a log P or 1-4 ? is this drug bioavailable ?

  yes

  medium permeability

  high solubility

  low metabolism
• what is the permeability, solubility and metabolism like for compounds that are very lipophilic and very highly ionised ?

  low permeability

  medium solubility

  high metabolism (very lipophilic)
• what type of characteristic does a drug being used for parenteral administration need to have and why is permeability not relevant here ?

  high solubility and not relevant as it is being administered directly into the bloodstream
• why do CNS drugs need higher permeability ?

  to get through BBB therefore they need to be smaller and less ionised
• why do zwitterions have poor membrane permeability eventhough they are neutral (no net charge)?

  the molecule still contains charges that will form strong bonding interactions with water therefore this reduces its log p and makes it not very lipophilic so has low permeability
• how can polar drugs enter the CNS ?

  active uptake by active transporters
• what is the permeability, solubility and metabolism like for drugs that are unionised but have a log p >4 ?

  high permeability (lipophilic)

  low solubility

  high metabolism
• what is the permeability, solubility and metabolism like for drugs that are moderately ionised (pka 3-12) and lop p >4 ?

  high permeability

  low solubility

  high metabolism
• what is the permeability, solubility and metabolism like for drugs that have moderate ionisation (pka 3-12) and a log p between 1 and 4 ?

  high solubility

  medium permeability

  low metabolism
• what is the permeability, solubility and metabolism like for drugs that have log p >4 and ionisation <3 or >12 ?

  low permeability

  medium solubility

  high metabolism
• what is the permeability, solubility and metabolism like for drug molecules that have log p <1 and and pka of <3 or >12 ?

  low permeability

  high solubility

  low metabolism
• why are ester groups not used in long acting drugs ?

  they can be hydrolysed by esterases
• what groups are most stable than esterases and therefore give a longer duration of action ?

  amides
• what is the definition of a prodrug ?

  a compound that is chemically altered in the body before exhibiting its desired pharmacological effects
• what are the uses of prodrugs ?

  to improve membrane permeability

  to prolong activity

  to mask toxicity and side effects

  to increase water solubility

  to target drugs to specific tissues
• what are the uses of ester prodrugs ?

  •Used to mask polar and ionisable carboxylic acids

  • Hydrolysed in blood or cells by esterases (structure can determine which) to the active form

  • Typically used when a carboxylic acid is required for target binding

  • Leaving group (alcohol) should be non toxic

  enalapril (prodrug had an ester group which gets converted to a carboxylic acid)- Enalaprit

  
• enalapril

  the prodrug of Enalaprit

  
• How can prodrugs increase passive permeability ?

  by masking ionisation of ionisable groups that decrease drug lipophilicity and therefore permeability
• what group do ester groups in prodrugs commonly mask the charge of ?

  carboxylic acid group
• prodrugs mask ionisation what else can they do ?

  alter solubility- this can enable the route of administration of drugs to be changed to extend the duration of action of drugs