Prodrug
Encyclopedia
A prodrug is a pharmacological
substance (drug
) administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised
in vivo
into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion (ADME
) optimization. Prodrugs are usually designed to improve oral bioavailability
, with poor absorption from the gastrointestinal tract
usually being the limiting factor.
Additionally, the use of a prodrug strategy increases the selectivity of the drug for its intended target. An example of this can be seen in many chemotherapy
treatments, in which the reduction of adverse effects is always of paramount importance. Drugs used to target hypoxic
cancer cells, through the use of redox
-activation, utilise the large quantities of reductase
enzyme
present in the hypoxic cell to bioactivate the drug into its cytotoxic form, essentially activating it. As the prodrug has low cytotoxicity prior to this activation, there is a markedly lower chance of it "attacking" healthy, non-cancerous cells which reduces the side-effects associated with these chemotherapeutic agents.
In rational drug design, the knowledge of both chemical properties likely to improve absorption and the major metabolic pathways in the body is used to modify the structure of new chemical entities for improved bioavailability. Conversely, the creation of prodrugs is sometimes unintentional, for example with serendipitous
drug discoveries, where the drug is only later identified as a prodrug after extensive drug metabolism studies.
Type IA prodrugs include many antimicrobial and chemotherapy agents (e.g., 5-flurouracil). Type IB agents rely on metabolic enzymes, especially in hepatic cells, to bioactivate the prodrugs intracellularly to active drugs. Type II prodrugs are bioactivated extracelluarly, either in the milieu of GI fluids (Type IIA), within the systemic circulation and/or other extracellular fluid compartments (Type IIB), or near therapeutic target tissues/cells (Type IIC), relying on common enzymes such as esterases and phosphatases or target directed enzymes. Importantly, prodrugs can belong to multiple subtypes (i.e., Mixed-Type). A Mixed-Type prodrug is one that is bioactivated at multiple sites, either in parallel or sequential steps. For example, a prodrug, which is bioactivated concurrently in both target cells and metabolic tissues, could be designated as a “Type IA/IB” prodrug (e.g., HMG Co-A reductase inhibitors and some chemotherapy agents; note the symbol “ / ” applied here). When a prodrug is bioactivated sequentially, for example initially in GI fluids then systemically within the target cells, it is designated as a “Type IIA-IA” prodrug (e.g., tenofovir disoproxil fumarate; note the symbol “ - ” applied here). Many ADEPs, VDEPs, GDEPs and futuristic nanoparticle- or nanocarrier-linked drug moieties can understandably be Sequential Mixed-Type prodrugs. To differentiate these two Subtypes, the symbol dash “ - ” is used to designate and to indicate sequential steps of bioactivation, and is meant to distinguish from the symbol slash “ / ” used for the Parallel Mixed-Type prodrugs.
Adapted from Pharmaceuticals (2:77-81, 2009) and Toxicology (236:1-6, 2007).
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
substance (drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
) administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion (ADME
ADME
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
) optimization. Prodrugs are usually designed to improve oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
, with poor absorption from the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
usually being the limiting factor.
Additionally, the use of a prodrug strategy increases the selectivity of the drug for its intended target. An example of this can be seen in many chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
treatments, in which the reduction of adverse effects is always of paramount importance. Drugs used to target hypoxic
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
cancer cells, through the use of redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
-activation, utilise the large quantities of reductase
Reductase
-Examples:* 5-alpha reductase* Dihydrofolate reductase* HMG-CoA reductase* Methemoglobin reductase* Ribonucleotide reductase* Thioredoxin reductase* E. coli nitroreductase* Methylenetetrahydrofolate reductase...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
present in the hypoxic cell to bioactivate the drug into its cytotoxic form, essentially activating it. As the prodrug has low cytotoxicity prior to this activation, there is a markedly lower chance of it "attacking" healthy, non-cancerous cells which reduces the side-effects associated with these chemotherapeutic agents.
In rational drug design, the knowledge of both chemical properties likely to improve absorption and the major metabolic pathways in the body is used to modify the structure of new chemical entities for improved bioavailability. Conversely, the creation of prodrugs is sometimes unintentional, for example with serendipitous
Serendipity
Serendipity means a "happy accident" or "pleasant surprise"; specifically, the accident of finding something good or useful without looking for it. The word has been voted as one of the ten English words hardest to translate in June 2004 by a British translation company. However, due to its...
drug discoveries, where the drug is only later identified as a prodrug after extensive drug metabolism studies.
Classification
Prodrugs can be classified into two major types, based on their cellular sites of bioactivation into the final active drug form, with Type I being those that are bioactivated intracellularly (e.g., anti-viral nucleoside analogs, lipid-lowering statins,), and Type II being those that are bioactivated extracellularly, especially in digestive fluids or the systemic circulation (e.g., etoposide phosphate, valganciclovir, fosamprenavir, antibody-, gene- or virus-directed enzyme prodrugs [ADEP/GDEP/VDEP] for chemotherapy or immunotherapy). Both types can be further categorized into Subtypes, i.e. Type IA, IB and Type IIA, IIB, and IIC based on whether or not the intracellular bioactivating location is also the site of therapeutic action, or the bioactivation occurs in the gastrointestinal (GI) fluids or systemic circulation (see Table 1).Type IA prodrugs include many antimicrobial and chemotherapy agents (e.g., 5-flurouracil). Type IB agents rely on metabolic enzymes, especially in hepatic cells, to bioactivate the prodrugs intracellularly to active drugs. Type II prodrugs are bioactivated extracelluarly, either in the milieu of GI fluids (Type IIA), within the systemic circulation and/or other extracellular fluid compartments (Type IIB), or near therapeutic target tissues/cells (Type IIC), relying on common enzymes such as esterases and phosphatases or target directed enzymes. Importantly, prodrugs can belong to multiple subtypes (i.e., Mixed-Type). A Mixed-Type prodrug is one that is bioactivated at multiple sites, either in parallel or sequential steps. For example, a prodrug, which is bioactivated concurrently in both target cells and metabolic tissues, could be designated as a “Type IA/IB” prodrug (e.g., HMG Co-A reductase inhibitors and some chemotherapy agents; note the symbol “ / ” applied here). When a prodrug is bioactivated sequentially, for example initially in GI fluids then systemically within the target cells, it is designated as a “Type IIA-IA” prodrug (e.g., tenofovir disoproxil fumarate; note the symbol “ - ” applied here). Many ADEPs, VDEPs, GDEPs and futuristic nanoparticle- or nanocarrier-linked drug moieties can understandably be Sequential Mixed-Type prodrugs. To differentiate these two Subtypes, the symbol dash “ - ” is used to designate and to indicate sequential steps of bioactivation, and is meant to distinguish from the symbol slash “ / ” used for the Parallel Mixed-Type prodrugs.
| Type | Bioactivation site | Subtype | Tissue location of bioactivation | Examples |
|---|---|---|---|---|
| Type I | Intracellular | Type IA | Therapeutic target tissues/cells | Acyclovir, 5-Flurouracil, Cyclophosphamide Cyclophosphamide Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group.... , Diethylstilbestrol diphosphate, L-Dopa, 6-Mercaptopurine, Mitomycin C, Zidovudine Zidovudine Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine.... |
| Type I | Intracellular | Type IB | Metabolic tissues (liver, GI mucosal cell,lung etc) | Carbamazepine Carbamazepine Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia... , Captopril Captopril Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the... , Carisoprodol Carisoprodol Carisoprodol is a centrally-acting skeletal muscle relaxant. Carisoprodol is slightly soluble in water and freely soluble in alcohol, chloroform and acetone. The drug's solubility is practically independent of pH. Carisoprodol is manufactured and marketed in the United States by Meda Pharmaceuticals... , Heroin, Molsidomine Molsidomine Molsidomine is an orally active, long acting vasodilating drug. Molsidomine is metabolized in the liver to the active metabolite SIN-1. SIN-1 is an unstable compound that releases nitric oxide upon decay as the actual vasodilating compound.- Chemistry :... , Paliperidone Paliperidone Paliperidone , also known as 9-hydroxyrisperidone, is an atypical antipsychotic developed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing... , Phenacetin Phenacetin Phenacetin is an analgesic, once widely used; its use has declined because of its adverse effects.-History:Phenacetin was introduced in 1887, and was used principally as an analgesic, and was one of the first synthetic fever reducers to go on the market... , Primidone Primidone Primidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants... , Psilocybin Psilocybin Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as... , Suldinac, Tetrahydrofurfuryl disulfide |
| Type II | Extracellular | Type IIA | GI fluids | Lisdexamfetamine, Loperamide oxide, Oxyphenisatin, Sulfasalazine |
| Type II | Extracellular | Type IIB | Systemic circulation and Other Extracellular Fluid Compartments | Acetylsalicylate, Bacampicillin Bacampicillin Bacampicillin is a penicillin antibiotic. It is a prodrug of ampicillin with improved oral bioavailability.It is sold under the brand names Spectrobid and Penglobe .... , Bambuterol Bambuterol Bambuterol is a long acting beta-adrenoceptor agonist used in the treatment of asthma; it also is a prodrug of terbutaline. Commercially, the AstraZeneca pharmaceutical company produces and markets bambuterol as Bambec and Oxeol .... , Chloramphenicol succinate, Dihydropyridine pralixoxime, Dipivefrin, Fosphenytoin Fosphenytoin Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures.... |
| Type II | Extracellular | Type IIC | Therapeutic Target Tissues/Cells | ADEPT ADEPT ADEPT is a strategy to overcome the problems of lack of tumor selectivity. An antibody designed/developed against a tumor antigen is linked to an enzyme and injected to the blood, resulting in selective binding of the enzyme in the tumor... s, GDEPs, VDEPs |
Examples
- 6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine in vivo.
- CarisoprodolCarisoprodolCarisoprodol is a centrally-acting skeletal muscle relaxant. Carisoprodol is slightly soluble in water and freely soluble in alcohol, chloroform and acetone. The drug's solubility is practically independent of pH. Carisoprodol is manufactured and marketed in the United States by Meda Pharmaceuticals...
is metabolized into meprobamateMeprobamateMeprobamate is a carbamate derivative which is used as an anxiolytic drug...
. Carisoprodol is not a controlled substance in the United States, but meprobamate is classified as a potentially addictive controlled substanceControlled substanceA controlled substance is generally a drug or chemical whose manufacture, possession, or use are regulated by a government. This may include illegal drugs and prescription medications ....
that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug. - EnalaprilEnalaprilEnalapril is an angiotensin converting enzyme inhibitor used in the treatment of hypertension and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in...
is bioactivated by esteraseEsteraseAn esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.A wide range of different esterases exist that differ in their substrate specificity, their protein structure, and their biological function.- EC classification/list...
to the active enalaprilatEnalaprilatEnalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and was developed partly to overcome these limitations of captopril...
. - Valaciclovir is bioactivated by esterase to the active aciclovirAciclovirAciclovir or acyclovir , chemical name acycloguanosine, abbreviated as ACV,is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, and Zovir...
. - FosamprenavirFosamprenavirFosamprenavir , under the trade names Lexiva and Telzir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. The FDA approved it October 20, 2003, while the EMEA approved it on July 12, 2004...
is hydrolysed to the active amprenavir. - LevodopaLevodopaL-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
is bioactivated by DOPA decarboxylase to the active dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. - ChloramphenicolChloramphenicolChloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
succinate ester is used as an intravenous prodrug of chloramphenicol, because pure chloramphenicol does not dissolve in water. - PsilocybinPsilocybinPsilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
is dephosphorylated to the active psilocinPsilocinPsilocin , an aromatic compound, sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin...
. - Heroin is deacetylated by esterase to the active morphineMorphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
. - MolsidomineMolsidomineMolsidomine is an orally active, long acting vasodilating drug. Molsidomine is metabolized in the liver to the active metabolite SIN-1. SIN-1 is an unstable compound that releases nitric oxide upon decay as the actual vasodilating compound.- Chemistry :...
is metabolized into SIN-1MolsidomineMolsidomine is an orally active, long acting vasodilating drug. Molsidomine is metabolized in the liver to the active metabolite SIN-1. SIN-1 is an unstable compound that releases nitric oxide upon decay as the actual vasodilating compound.- Chemistry :...
which decomposes into the active compound nitric oxideNitric oxideNitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
. - PaliperidonePaliperidonePaliperidone , also known as 9-hydroxyrisperidone, is an atypical antipsychotic developed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing...
is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidoneRisperidoneRisperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
. - PrednisonePrednisonePrednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
, a synthetic cortico-steroidCorticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
drug, is bioactivated by the liver into the active drug prednisolonePrednisolonePrednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
, which is also a steroid. - PrimidonePrimidonePrimidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
is metabolized by cytochrome P450 enzymes into phenobarbitalPhenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, which is major, and phenylethylmalonamidePhenylethylmalonamidePhenylethylmalonamide is a metabolite of primidone....
, which is minor. - DipivefrineDipivefrineDipivefrine is a prodrug of epinephrine used to treat glaucoma. It is available as ophthalmic solution. It causes vasoconstriction, decreased aqueous humor production, and decreases intraoccular pressure. It is converted to epinephrine upon penetration of the cornea....
, given topically as an anti-glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
drug, is bioactivated to epinephrineEpinephrineEpinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
. - Lisdexamfetamine is metabolized in the small intestine to produce dextroamphetamineDextroamphetamineDextroamphetamine is a psychostimulant drug which is known to produce increased wakefulness and focus as well as decreased fatigue and decreased appetite....
at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorderAttention-deficit hyperactivity disorderAttention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and... - Diethylpropion is a diet pill that does not become active as a monoamine releaser or reuptake inhibitor until it has been N-dealkylated to ethylpropion.
- FesoterodineFesoterodineFesoterodine is an antimuscarinic drug developed by Schwarz Pharma AG to treat overactive bladder syndrome . It was approved by the European Medicines Agency in April 2007 and was approved by the US Food and Drug Administration on October 31, 2008.Fesoterodine is a prodrug...
is an antimuscarinic that is bioactivated to tolterodineTolterodineTolterodine is an antimuscarinic drug that is used to treat urinary incontinence.It is marketed by Pfizer in Canada and the United States by its brand name Detrol. In Egypt it is also found under the trade names Tolterodine by Sabaa and Incont L.A...
. - Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).