Prodrug

A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug.^[1][2] Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. Instead of administering a drug directly, a prodrug might be used instead to improve how a medicine is absorbed, distributed, metabolized, and excreted (ADME).^[3][4] Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract.^[1] A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This reduces adverse or unintended effects of a drug, especially important in treatments like chemotherapy, which can have severe unintended and undesirable side effects.

IUPAC definition

Compound that undergoes biotransformation before exhibiting pharmacological
effects.

Note 1: Modified from ref.^[2]

Note 2: Prodrugs can thus be viewed as drugs containing specialized nontoxic
protective groups used in a transient manner to alter or to eliminate undesirable
properties in the parent molecule.^[5]

History

Many herbal extracts historically used in medicine contain glycosides (sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailable aglycone. For example, salicin is a β-D-glucopyranoside that is cleaved by esterases to release salicylic acid. Aspirin, acetylsalicylic acid, first made by Felix Hoffmann at Bayer in 1897, is a synthetic prodrug of salicylic acid.^[6][7] However, in other cases, such as codeine and morphine, the administered drug is enzymatically activated to form sugar derivatives (morphine-glucuronides) that are more active than the parent compound.^[1]

The first synthetic antimicrobial drug, arsphenamine, discovered in 1909 by Sahachiro Hata in the laboratory of Paul Ehrlich, is not toxic to bacteria until it has been converted to an active form by the body. Likewise, prontosil, the first sulfa drug (discovered by Gerhard Domagk in 1932), must be cleaved in the body to release the active molecule, sulfanilamide. Since that time, many other examples have been identified.

Terfenadine, the first non-sedating antihistamine, had to be withdrawn from the market because of the small risk of a serious side effect. However, terfenadine was discovered to be the prodrug of the active molecule, fexofenadine, which does not carry the same risks as the parent compound. Therefore, fexofenadine could be placed on the market as a safe replacement for the original drug. Loratadine, another non-sedating antihistamine, is the prodrug of desloratadine, which is largely responsible for the antihistaminergic effects of the parent compound. However, in this case the parent compound does not have the side effects associated with terfenadine, and so both loratadine and its active metabolite, desloratadine, are currently marketed.^[8]

Classification

Prodrugs can be classified into two major types,^[9] based on how the body converts the prodrug into the final active drug form:

• Type I prodrugs are bioactivated inside the cells (intracellularly). Examples of these are anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering statins.
• Type II prodrugs are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body's circulatory system, particularly in the blood. Examples of Type II prodrugs are salicin (described above) and certain antibody-, gene- or virus-directed enzyme prodrugs used in chemotherapy or immunotherapy.

Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation system. See Table 1 below for further subtype categorization.^[9]

Subtypes

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; note the symbol " - " applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies (ADEPTs, VDEPTs, GDEPTs) and proposed nanoparticle- or nanocarrier-linked drugs 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 (see Table 1 in Wu, K.M.^[9] and Table 1 in Wu and Farrelly).^[10]

Table 1: Classification of prodrugs

Type	Bioactivation site	Subtype	Tissue location of bioactivation	Examples
Type I	Intracellular	Type IA	Therapeutic target tissues/cells	Aciclovir, fluorouracil, cyclophosphamide, diethylstilbestrol diphosphate, L-DOPA, mercaptopurine, mitomycin, zidovudine
		Type IB	Metabolic tissues (liver, GI mucosal cell, lung etc.)	Carbamazepine, captopril, carisoprodol, heroin, molsidomine, leflunomide, paliperidone, phenacetin, primidone, psilocybin, sulindac, fursultiamine, codeine
Type II	Extracellular	Type IIA	GI fluids	Loperamide oxide, oxyphenisatin, sulfasalazine
		Type IIB	Systemic circulation and other extracellular fluid compartments	Acetylsalicylate, bacampicillin, bambuterol, chloramphenicol succinate, dipivefrin, fosphenytoin, lisdexamfetamine, pralidoxime
		Type IIC	Therapeutic target tissues/cells	ADEPTs, GDEPTs, VDEPTs

Adapted from Pharmaceuticals (2:77-81, 2009) and Toxicology (236:1-6, 2007).

Examples

• Aspirin
• 6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine in vivo.
• ALD-52 and MLD-41 will both convert into the active psychedelic LSD-25.
• BL-1020 (perphenazine 4-aminobutanoate trimesylate) is converted into perphenazine and GABA into the brain.
• Carisoprodol is metabolized into meprobamate. Until 2012, carisoprodol was not a controlled substance in the United States, but meprobamate was classified as a potentially addictive controlled substance that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug.
• Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol, because pure chloramphenicol does not dissolve in water.
• Codeine is converted into morphine by cytochrome P450 enzyme CYP2D6.
• Cyclophosphamide is a prodrug activated by liver cytochrome P450 (CYP) enzymes to form the metabolite 4-hydroxy cyclophosphamide.
• 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.
• Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine.
• Enalapril is bioactivated by esterase to the active enalaprilat.
• Fenofibrate is an isopropyl ester of fenofibric acid.
• Fesoterodine is an antimuscarinic that is bioactivated to 5-hydroxymethyl tolterodine, the principle active metabolite of tolterodine.
• Fosamprenavir is hydrolyzed to the active amprenavir.
• Fospropofol is metabolized by alkaline phosphatases to an active metabolite, propofol.
• Heroin is deacetylated by esterase to the active morphine.
• Latanoprost is an isopropyl ester, that is hydrolyzed by esterases in the cornea to the biologically active acid.
• Leflunomide is rapidly metabolized to the active teriflunomide in the gut wall and liver.
• Levodopa is bioactivated by DOPA decarboxylase to the active dopamine.
• Lisdexamfetamine is L-lysyl amide that is metabolized in the small intestine to dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder
• Molsidomine is metabolized into linsidomine which decomposes into the active compound nitric oxide.
• Mycophenolate mofetil is an ester of mycophenolic acid used in transplant medicine.
• Olmesartan medoxomil is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
• Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase.
• Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone.
• Prednisone, a synthetic corticosteroid drug, is bioactivated by the liver into the active drug prednisolone, which is also a steroid.
• Primidone is metabolized by cytochrome P450 enzymes into phenobarbital, which is major, and phenylethylmalonamide, which is minor.
• Psilocybin is dephosphorylated to the active psilocin.
• Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).
• Valaciclovir is bioactivated by esterase to the active aciclovir.
• Ximelagatran is dealkylated and dehydroxylated to the active melagatran.

See also

• Active metabolite
• Codrug
• Toxification

References

1. Miles Hacker, William S. Messer II, Kenneth A. Bachmann Pharmacology: Principles and Practice. Academic Press, Jun 19, 2009. pp. 216-217.
2. C. G. Wermuth, C. R. Ganellin, P. Lindberg, L. A. Mitscher; Ganellin; Lindberg; Mitscher (1998). "Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)". Pure and Applied Chemistry. 70 (5): 1129. doi:10.1351/pac199870051129.
3. Malhotra, B; Gandelman, K; Sachse, R; Wood, N; Michel, M. C. (2009). "The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine". Curr Med Chem. 16 (33): 4481–9. doi:10.2174/092986709789712835. PMID 19835561.
4. Stella, VJ; Charman, WN; Naringrekar, VH (1985). "Prodrugs. Do they have advantages in clinical practice?". Drugs. 29 (5): 455–73. doi:10.2165/00003495-198529050-00002. PMID 3891303.
5. Vert, Michel; Doi, Yoshiharu; Hellwich, Karl-Heinz; Hess, Michael; Hodge, Philip; Kubisa, Przemyslaw; Rinaudo, Marguerite; Schué, François (2012). "Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)" (PDF). Pure and Applied Chemistry. 84 (2): 377–410. doi:10.1351/PAC-REC-10-12-04.
6. Sneader, W. (2000). "The discovery of aspirin: A reappraisal". BMJ (Clinical research ed.). 321 (7276): 1591–1594. doi:10.1136/bmj.321.7276.1591. PMC 1119266. PMID 11124191.
7. Karsten Schrör (2009). Acetylsalicylic acid. ISBN 978-3-527-32109-4.
8. UK Medicines Information Pharmacists Group. New Medicines on the Market: Desloratidine. June 2001.
9. Wu, Kuei-Meng (2009). "A New Classification of Prodrugs: Regulatory Perspectives". Pharmaceuticals. 2 (3): 77–81. doi:10.3390/ph2030077.
10. Wu, K.M.; Farrelly, J. (2007). "Regulatory Perspectives of Type II Prodrug Development and Time-Dependent Toxicity Management: Nonclinical Pharm/Tox Analysis and the Role of Comparative Toxicology". Toxicology. 236 (1-2): 1–6. doi:10.1016/j.tox.2007.04.005.

External links

• Special Issue on Prodrugs: from Design to Applications