Pro-drugs Flashcards
Most common method of drugs crossing cells
Passive diffusion through the phospholipid bilayer
The rate of passive diffusion is governed by three factors:
The concentration gradient across the membrane
The partition coefficient P for the drug between the lipid phase of the cell membrane and the aqueous phases either side
For very large molecules, increasing molecular size also slows down membrane penetration
What is lipophilicity?
This represent s the preference for a drug molecule to dissolve in the lipid phase of the cell membrane rather than aqueous phases
What determines lipophilicity?
The structural components of a molecule- polar groups reduce lipophilicity
The cell membrane is very difficult to work with experimentally, what is used to approximate it?
In most cases a simple organic hydrophobic solvent is used, and the partition between this solvent and water is measured
Octanol is often used as the lipid
Simplest experiment for lipophilicity?
A drug sample is partitioned between layers of octanol and water, and the concentration of sample in each layer is measured
Measurement of logP
P= concentration in organic octanol layer/ concentration in aqueous layer
Often represented as Log10P
Other solvents (not octanol) that can be used
Particularly for CNS-acting drugs, where access may be especially difficult, combined figures for octanol/water and cyclohexane/water may be more reliable
Acidic/basic drugs
If a drug molecule may be protonated at or near physiological pH, its lipophilicity will vary greatly with the pH of measurement
The ionised form of a drug will have a much lower P than the unionised form, this may be approached by using buffer pH 7.4 in place of water
What is logD?
LogD describes the ratio of the concentrations of all forms of the compound (ionised plus unionised) in each of the two phases (normally at pH 7.4)
How to easily modify a chemical structure to raise the logP?
Block polar functional groups e.g. acid with less polar functional groups e.g. ester, hydrocarbon side chain
Effects of logP being too high/low
If P is low, passive diffusion will be slow and drug action limited
If P is too high the majority of drug may reside in the lipid phase, far from the site of action, and correlates with very poor watersolubility
Optimum logP
Between 1 and 2 is often regarded as ideal for many drug sites
Lipinski’s rule suggest lower than 5 for good absorption
How can drugs with much lower logP access tissues?
The aqueous pore route (entry via gaps between cells), only generally effective for small molecules
Active (specific) membrane transport systems, generally effective for drugs which resemble natural metabolites e.g. nucleosides, peptides
In case of a failed drug delivery to target tissue, three approaches may work:
Pharmaceutical technologies
Analogue synthesis
Pro-drug synthesis
What is analogue synthesis?
An initial failed lead drug may be very greatly improved in terms of drug access by the synthesis of close structural analogues
Solubility, lipophilicity, stability to metabolism etc. can all be modified by analogue synthesis
However, it is very easy to simultaneously lose potency at the drug target
Very demanding on resources
What is a pro-drug?
A pro-drug is a molecular derivative of a drug which requires structural transformation in vivo to exert its pharmacological action
Advantages of pro drugs (5):
Improved tissue penetration by altered lipophilicity and or solubility
Reduced first pass metabolism improving bioavailability
Selective transformations of pro-drug in target tissue may reduce or remove unwanted systemic effects of drug
Altered pharmacokinetics e.g. altered duration of action
Improved pharmaceutics e.g. reduced GI irritation
Disadvantages of pro-drugs (5):
More complex- more to worry about
Possible chemical instability/ storage problems
Interspecies variability of metabolism
Possible extra toxicity of pro-drug or moiety
Extra production costs
Pro-drugs derived from carboxylic acids (not examples!)
Several different structural types e.g. esters, amides etc.
Either the acid or the other component can be the pro-drug
Protection of these structural features is often desirable as it increases lipophilicity
Many enzyme systems are capable of ester/ amide hydrolysis to release the drug
Simple aromatic and aliphatic ester pro-drugs
Very popular as easy to prepare, relatively chemically stable, and pro-moiety often non-toxic
e.g. drug- enalaprilat, pro-drug- enalapril
Enalaprilat ahs <12% absorption, while enalapril has 50-75% absorption due to a higher logP
Difference between pro-drug and drug
The pro-drug is the one you take, the drug is the active form
Amides as pro-drugs
Less popular than esters due to the slow rate of in vivo hydrolysis of amides (regeneration of drug from pro-drug)
Exceptions involve the use of amino acids/peptides or other substituted amides
Pro-drugs derived from inorganic acids
Sulphuric and phosphoric acid derivatives have been used a pro-drugs, largely these are used to increase water solubility rather than lipophilicity
Clindamycin/ clindamycin phosphate
The phosphate gives much reduced pain at the injection site, in vivo half life of 10 minutes
Fludarabine
Fludarabine monophosphate is a useful oral pro-drug of fludarabine; the patent life of the parent drug was thus extended
Dose- by mouth, adult 40mg/m2 for 5 days every 28 days usually for 6 cycles
Fospropofol
Fospropofol is a water soluble sedative/ anaesthetic, which is transformed with alkaline phosphatase to make propofol
Pro-drugs activated by oxidation/ reduction
Oxidative/ reductive enzyme systems are widely distributed and are finding increasing use in pro-drugs
Sulindac, which makes sulindac sulphide, has 100x the water solubility of the drug and less GI toxicity
Pro-2-PAM
Pro-2-PAM has vastly improved BB penetration, leading to a selective concentraion in the brain due to the oxygen rich environment, compared to 2-PAM (pralidoxine)
Site specific delivery of pro-drugs
One of the most promising aspects of pro-drugs is the possibility to achieve site-specific delivery of the active drug following systemic administration of the pro-drug
In principle this could greatly improve the pharmacological potency, whilst removing unwanted systemic effects (toxicities)
In practice, the full potential of this approach has yet to be achieved
Requirements for site specific delivery of pro-drugs (4)
Rapid transport/uptake at site of action
No cleavage of pro-moiety at liver, kidney etc.
Efficient cleavage at site of action
Retention of drug at active site for a reasonable period
Site specific delivery of dopamine
Dopamine has a wide array of pharmacological effects at many tissue sites
Its vasodilating effects in the liver could be useful in the treatment of shock if it could be delivered selectively
Glutamyl transpeptidase has high activity in the liver, if we can design a dopamine pro-moiety to be cleaved by this enzyme system we may achieve liver selectivity
The dopamine is selectively generated from the glutamyl dopamine in the liver
The potent pharmacological effects of the drug are thus concentrated in the liver
Site specific delivery of hexamine
Hexamine acts as a pro-drug of formaldehyde, which is too toxic for systemic use, but achieves site-selective delivery
The pro-drug reversion is chemical mediated, not enzymatic
In the acidic environment of the urine, the tricyclic amine hydrolyses, to liberate the anti-bacterial formaldehyde
To prevent hydrolysis in the stomach an enteric coated tablet must be used
ADEPT
Antibody-directed enzyme pro-drug therapy
An activating enzyme is attached to a tumour cell antibody
A pro-drug is the administered that requires this enzyme for activation, pro-drug activation is then confined to the region of the tumour cell
Antibody-linked cytosine deaminase leads to a 17-fold increase in tumour cells following FC dosing, vs. FU dosing alone
Site specific delivery of cyclophosphamide
Cyclophosphamide first undergoes an enzyme catalysed activation step, hydroxylation by liver microsomes
This material spontaneously rearranges to a ring opened isomer
Which finally undergoes a chemical beta elimination to yield the actual drug
AZT
AZT is entirely inactive and requires three consecutive phosphorylations to the triphosphate in order to be active
Thus, AZT is a pro-drug of AZT-triphosphate, which is common to all nucleoside drugs
Problems of nucleoside drugs (5)
Often poor metabolism to the active triphosphates Deactivation, chemical or enzymatic Structure based/ RDD difficult Clinical toxicities Emergence of resistant virus (tumour)
