Prodrug Definition (and controversy surrounding it)
- prodrugs are inactive drugs that undergo a chemical or biochemical conversion to the active drug.
- Some consider various injectable salt forms to be prodrugs (Insulin).
- Others argue that an inactive drug that is “activated” by a change in pH rather than an enzymatic event is also a prodrug (Omeprazole)
- Are active drugs whose metabolites also circulate and are also active then prodrugs as well? Many examples of this are known (Prozac, Diltiazem). Since terfenadine did not achieve measurable levels in the blood in man was it just a toxic prodrug and the metabolite the real drug?
Approximately 7-10% of marketed drugs are considered to be prodrugs and the number is increasing. Two major reasons:
- Circumvent problems delivering a new drug
- poor bioavailablity and toxicity of the parent drug.
- Improve the efficacy of older drugs, usually to improve absorption.
- poor bioavailablity and toxicity of the parent drug.
Where do the bioconversion occur? Major locations include:
1. Liver (major)
2. GI tract lumen and enterocytes
4. Target Cell (Intracellular and Cell Surface) 5. At the site of a depot injection.
What enzymes catalyze the bioconversion reactions?
1. Carboxylesterases and phosphoesterases
2. Cytochrome P450 enzymes
4. Others (anticancer drugs)
What are some of the downsides to using enzymes to create active drugs from inactive prodrugs.
- The enzyme may be subject to polymorphisms where the PM’s are unable to get therapeutic benefit.
- Polytherapy may lead to inhibition of the “activating” enzyme by other drugs (a type of DDI).
- The presence of ionizable groups on a drug can hinder bioavailability since drugs that are ionized at physiological pH do not pass through membranes that line the GI tract.
- Active drug has two ionizable groups and is a zwitterion. Hence absorption/bioavailability is very poor.
- The ethyl ester is reasonably well absorbed and undergoes rapid first pass hydrolysis by carboxylesterases that are present in the liver.
- Carboxylic acid is retained in the active drug after cleavage of the ester bond
- Fluphenazine (antipsychotic, schizophrenia) Orally, this active drug is administered three times a day which can be a problem in compliance.
- The fluphenazine esters ((n=5 is the heptanoate ester; n=8 is the decanoate ester) are the inactive prodrugs. Note the effect of chain length on the dosing interval. (n=5, 1-2 wks, n=8, 2-3 wks)
- They are very poorly soluble in water and are injected in a bolus IM. The esters slowly diffuse from the bolus site into the blood.
- Bioactivation of the prodrug occurs in the blood by blood esterases.
- Acid fragment that is produced by the esterase is “thrown away”. The active drug is the alcohol fragment and bit that can be administered orally.
- This ester depot strategy is also used with some of the steroids.
- Enaloprat ACE inhibitor but was only effective IV (note it has two carboxylates and both are required for activity).
- Made the inactive ethyl ester (Enalapril) which was absorbed and converted to the acid by carboxylesterases in the liver.
- All but one of the ACE inhibitors on the market have the required two carboxylate groups of enaloprat where one of the carboxylates is the ethyl ester. Thus they are all prodrugs.
Tripeptide transporter is normally used to bring in small peptides from protein proteolysis in the GI tract.
- Valtrex was made in order to increase AUC to acyclovir and highlighted the tripeptide transporter as a potential way to increase bioavailability.
Ester hydrolysis in the liver provides the amino acid valine and acyclovir. This is another case where the alcohol fragment is the important product
- Acyclovir is a prodrug that is activated to the active agent intracellularly in the infected cells.
- The pyrrophosphorylated metabolite (acyclo-GTP) is formed much more rapidly by the viral thymidine kinase than mammalian thymidine kinase. This helps to protect uninfected cells.
- The acyclo-GTP is trapped inside the cell but is eventually degraded.
- 5 Fluorouracil (5-FU; Efudex) cancer drug that must be give iv and there are many serious side effects to the drug. 5-FU is actually a prodrug that is converted intracellularly to the active drug that inhibits thymidylate synthetase.
- The prodrug Capecitabine has good oral bioavailability and peaks around 1.5 hours after dose. 5-FU and 5’deoxy-5-fluoruridine levels peak around 2 hours and the latter accumulates with repeat dosing.
- Capecitabine apparently inhibits CYP2C9 and causes excessive bleeding with warfarin (Black Box Warning).
- carbamate hydrolysis by liver carboxylesterase
- Anticancer drugs that are classified as the nitrogen mustards. IV administration.
- They are bioactivated via a series of steps that is initiated by CYP450 (liver) catalyzed hydroxylation of a carbon adjacent a nitrogen in a rather unusual looking six membered ring to produce a carbinolamine which can exist in a ring opened form as well.
- These metabolites enter the cell and undergo a number of reactions that eventually produce aziridine structures. (A veritable orgy of electron pushing to get there). This is probably the proximate alkylating agent that reacts covalently with DNA.
- Here all of the intermediate compounds of the pathway are too short-lived to be formulated for administration.
Plavix and Prasugrel
- Orall. They inhibit platelet aggregation by irreversible binding of metabolites to the P2Y12 receptor.
- Before and after cardiac intervention procedures such a stent placemnet (percutaneous coronary intervention; PCI) to prevent clotting.
- Plavix generic. Prasugrel is expensive and higher risk of bleeding (Black Box Warning).
- There is a high interest in making better drugs.
- While both drugs are metabolized by esterases this reaction is used to clear plavix to inactive metabolites. By contrast the hydrolysis of the ester of prasugrel is required for the generation of the active compound.
- P450 enzymes catalyze two steps in the bioactivation of plavix. The first of these is catalyzed by CYP2C19 to produce a hydroxylated thiene ring. A Black Box Warning has been issued due to the risk for CYP2C19 PMs. We would also be worried about DDI’s with CYP2C19 inhibitors causing the same problem.
- By contrast the prasugrel was designed so the hydroxythiene was generated by an esterase reaction. In both causes the thiolactone metabolism is multi enzyme.
Pasugrel/Plavix colored Diagram
- Prasugrel: The first esterase step actually occurs mostly in the enterocytes. While this drug is well absorbed there is no parent prodrug in blood.
- Prasugrel and Plavix: There are multiple P450 enzymes that carry out the final oxidative ring opening of the thiolactone in the liver so there is not a major issue with polymorphisms or drugs that produce DDI’s. PON-1 is not important
- Plavix: The arrow between intestine and the color of the product of the arrow seem to indicate an esterase step. That is not true, Plavix enters the hepatocytes unchanged.
- Note that both released metabolites that are believed to be the real drug are irreversible inhibitors of P2Y12. The other indicated drugs or drug candidates are reversible inhibitors of P2Y12.
- L-DOPA (levodopa) orally for Parkinsonism and is inactive. L-DOPA bioavailability is 20-40%; note that it is an amino acid and is zwitterionic so it requires a transporter to cross membranes and be absorbed.
- L-DOPA and enzyme that catalyzes the conversion to dopamine participate in the normal pathway for the synthesis of dopamine in both the peripheral nervous system and the CNS. Thus L-DOPA levels are increased over normal levels when it is adminstered.
- L-DOPA crosses the blood brain barrier (BB) while dopamine does not.
- The increased conversion of the L-DOPA to dopamine in the peripheral nervous system causes unwanted side effects such as hypotension and nausea.
- L-DOPA is usually given with a second drug, Carbidopa which inhibits dopa decarboxylase. The inhibitory effects of Carbidopa are confined to the peripheral nervous system as Carbidopa cannot cross the blood brain barrier.