Lecture 20/21 Flashcards
Prodrugs
What makes a good drug?
- Good activity and selectivity on the right target
- ADMET
- Absorption (bioavailability), Distribution (plasma concentrations), Metabolism (inactive and active metabolites), Excretion (termination of drug action), and Toxicity (drug itself or its metabolites)
Problems with ADMET (5)
- Incomplete absorption
- Too rapid or slow of transportation of drug into body
- Incomplete systemic delivery of agent
- Toxicity problems
- Poor site specificity
Reasons for Prodrugs
- Bioavailability of many molecules is low due poor absorption or first pass metabolism
- Sometimes formulations can offset these drawbacks, but usually need a chemical solution like a prodrug to deal with the issues with ADMET
Prodrugs
- Inactive compounds that are converted to active compounds in the body
- 15% of the Top 100 Drugs
- Biotransformation must occur before pharmacologic effect can take place
- Bypasses paradox of lipophilic enough to pass membranes and water soluble enough to enter solution, be bioavailable, and transport through body
- Transform from a lipophilic, non-polar molecule to a water soluble more polar molecule usually
Prodrug Uses (6)
- Improving membrane permeability
- Prolonging activity
- Masking Toxicity and side effects
- Varying water solubility
- Drug targetting
- Improving chemical stability
Promoiety
- Inactive prodrug component that is lipophilic and non-polar
- Drug + promoiety are covalently linked
- Ideal is that the promoiety alone is non-toxic and that the parent drug is released in high recovery ratios
Prodrug Pharmaceutical Objectives (4)
- Increase solubility
- Increase chemical stability
- Improved taste and odor
- Decreased irritation and pain
Prodrug PK Objectives (4)
- Increase absorption
- Decrease presystemic metabolism
- Increased absorption by non-oral routes
- Improved prolonged duration of action
Prodrug PD Objectives (2)
- Masking of reactive agent to improve TI
2. In site activation of a cytotoxic agent
Are the prodrug objectives intertwined?
Yes
Prodrug Classifications
- Carrier-Linked
2. Bioprecursors
Carrier-Linked Prodrug Classifications
- Bipartite Prodrugs
- Tripartite Prodrugs
- Mutual Prodrugs
Carrier-Linked Prodrugs
- Contain temporary linkages between active substrate and a carrier group that improves physicochemical or PK properties
- Carrier group is easily removed in vivo (usually via hydrolysis)
- Carrier group must be non-toxic and biologically inactive when detached
Bioprecursor
-Compound that is metabolized by molecule modification into new compound that may also be active or further metabolized into an active metabolite
Carrier-Linked Advantages
- Increase absorption
- Injection site pain relief
- Elimination of unpleasant taste
- Decreased toxicity
- Decreased metabolic activation
- Increased chemical stability
- Prolonged or shortened action
Carrier-Linked Prodrug Design Goals
- Link between drug and promoiety usually done via a covalent bond
- Prodrug is inactive or less active than the parent molecule
- Link between drug and moiety broken in vivo
- Prodrug and in vivo promoiety must be non-toxic
- Generation of active form must be rapid to ensure drug levels are effective at site of action and to minimize alternative prodrug metabolism or inactivation
Bipartite Prodrugs
Drug —- Carrier
-One carrier group attached to drug
-Greatly modify lipophilicity due to attached carrier, released by hydrolytic cleavage
-Cleavage can be chemical or enzymatic in nature
EX: Tolmetin-glycine prodrug (Amtolmetin), formed by amidation of tolmetin and glycine
Tripartite Prodrugs
Drug —– Linking Structure —– Carrier
-Carrier group attached via a linker or spacer to drug
EX: Bacampicillin (prodrug of Ampicillin)
Mutual Prodrugs
-Two pharmacologically active agents coupled together so that they act as the promoiety for each other
-Bipartite or tripartite prodrug where the carrier is a synergistic drug with the drug it is linked with
EX: Benorylate (aspirin and paracetamol) or Sultamicillin (ampicillin and sulbactam when hydrolyzed)
Conversion of Prodrugs
- Metabolism (enzyme dependent)
- Chemical methods (non-dependent) - hydrolysis, decarboxylation, not patient dependent, more prone to storage/stability issues
Common Prodrug Functional Groups
- SH
- OH
- PO(OH)2
- NH
- C=O
- COOH
- Most prodrugs require a “synthetic” handle which are heteroatomic groups like those above
- Most common = ester
Ester
- Most common, 49% of prodrugs
- Can make a prodrug with -OH, -SH, or -COOH
- Increases lipophilicity mostly to increase permeability by masking charged groups
- Hydrolyzed by ubiquitous esterases in blood, liver, or other tissues/organs (EX: carboxylesterases, paraoxonases, etc.)
- OH and -COOH are the most common functional groups on the drug that are exposed after ester is broken
- *Allows for a wide choice of promoieties that vary in steric, electronic, and hydrophobicity properties. Allows rate and extent of hydrolysis to be controlled**
Improve Membrane Permeability
-Polar groups like COOH can’t pass membrane
-Masking functional groups to be less polar increases their permeability
-Esters are removed later with hydrolysis and the remaining promoiety should be non-toxic
EX: Enalapril has an ester added onto it to allow for oral administration. Two carboxylate groups were added to it, one of which is an ethyl ester. All ACEi’s except one have this
Candoxatril
- Prodrug of Candoxatrilat (protease inhibitor)
- 5-indanyl group is added to it to increase the rate of hydrolysis
- 5-indanyl group is also non-toxic on its own
- *Example of how different esters can vary the rate of hydrolysis**
Enhanced Absorption
- Ampicillin is only ~40% absorbed, what isn’t absorbed destroys the intestinal flora
- Pivampicillin - breaks up into formaldehyde and pivalic acid
- Bacampicillin - breaks up into acetaldehyde, ethanol, and carbon dioxide (natural metabolites, better tolerated)
- Both of the prodrug forms increase absorption up to ~98-99%, allows for a dose reduction that is equally effective as a larger dose of ampicillin
- Generation of ampicillin is also rapid and only takes ~15 minutes
- *Both prodrug forms are more lipophilic which makes them better absorbed and more stable in the gastric fluids to lead to better absorption**
Erythromycin
- Bitter and easily destroyed in acidic pH
- Propionate ester - increases lipid solubility for improved oral absorption (hydrolyzed for activity)
- Lauvyl sulfate salt - absorption not affected by food, less bitter after taste, and acid stable
Two different promoiety options depending on which characteristics you are trying to improve
Increased Opthalmic Absorption
- Epinephrine has limited use for glaucoma as an adrenergic agent since it is highly polar
- Dipivalyl derrivative (adds two t-butyl esters) increase the effectiveness by increasing its lipid solubility to get better corneal absorption
Increased Percutaneous Absorption
- Morphine susceptible to first pass metabolism
- Prodrugs increase its lipophilicity and enhance physicochemical properties to more readily cross skin for transdermal delivery
“Trojan Horse” Strategy
-Mimic biosynthetic building block
-Transported across membrane by carrier proteins (active transport)
EX: Dopamine and L-DOPA - dopamine is too polar to cross BBB, L-DOPA is MORE polar than dopamine but utilizes a carrier protein to get across BBB where it is decarboxylated to dopamine
Prolonged Activity Options
- Mask polar groups
- Add hydrophobic groups
- Slow release mechanisms
Masking Polar Groups
-Decreases elimination
EX: Azathioprine for 6-Mercaptopurine - 6-Mercaptopurine suppresses immune responses but is eliminated too quickly and has a short half life. Azathioprine slowly convert to 6-Mercaptopurine to allow for a longer lifetime
Adding Hydrophobic Groups
- Drug concentration in fat tissue
- Slow removal of hydrophobic groups
- Slow release carrier prodrugs are used as a basis for depot preparations administered by IM injection
Cycloguanil Pamoate
- Antimalarial
- Cycloguanil is bound ionically to anion containing a large, lipophilic group (pamoate)
- Slow, dissociation steps must occur before drug release
- Releases active group over months at therapeutic levels
Fluphenazine + Fatty Esters
- Antipsychotic
- OCO(CH2)6CH3
- Given by IM injection, poorly soluble in water
- Concentrated in fatty tissues, slowly diffuses into blood
- Slowly released into blood supply
- Rapid hydrolyzed in blood
- Fluphenazine alone has to be taken TID, potential compliance problem
- Esters increase the dosing interval to every 1-2 or 2-3 weeks depending on the length of the ester
Slow Release Mechanisms
-Often provided by slow hydrolysis of amide and fatty acid ester carriers
-Hydrolysis can vary from hours to weeks
EX: Use of glycine as a linker for anti-inflammatory tolmetin sodium. Increases the duration of its peak action from 1 to 9 hours
Mask Toxicity and Side Effects
-Masked groups - responsible for toxicity/side effects
-Used when groups are important for activity
EX: Aspirin for salicylic acid - salicylic acid is an analgesic that causes stomach ulcers due to its phenol group. Phenol is masked by an ester in aspirin which is later hydrolyzed in the body
Cyclophosphoramide
- Prodrug for Phosphoramide mustard (anticancer)
- Cyclophosphoramide is non-toxic and orally active
- Phosphoramide is an alkylating agent
- Converted in the liver by phosphoramidase
Decreased Water Solubility
-Reduces foul taste of orally active drug
-Less soluble on tongue
-Less revolting taste
EX: Palmitate ester for chloramphenicol (antibiotic)
Increased Water Solubility
-For IV drugs
-Increased concentration and reduced dose volume
-May decrease pain at site of injection
-Done by introducing ionizable groups like succinate, phosphate, or amino acid (lysine) esters or linking to neutral macromolecules
EX: Succinate ester for chloramphenicol (antibiotic) - chloramphenicol doesn’t dissolve in water, the addition of succinate will increase the rate of hydrolysis and thus increase the activation of the drug
Methylprednisolone
- Poorly soluble in water
- Esterfied with succinic or phosphoric acid to increase water solubility for IV (Solu-Medrol) or oral solution preparations
Lysine Ester of Oestrone
- Lysine ester of oestrone is better absorbed than oestrone
- Increases water solubility to prevent formulation of fat globules in the gut
- Better interaction with gut wall
- Hydrolysis in blood releases oestrone and leaves a non-toxic amino acid behind
