Prodrug: Difference between revisions
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* [[Latanoprost]] is an isopropyl ester, that is hydrolyzed by esterases in the [[cornea]] to the biologically active acid. |
* [[Latanoprost]] is an isopropyl ester, that is hydrolyzed by esterases in the [[cornea]] to the biologically active acid. |
||
* [[Olmesartan medoxomil]] is hydrolyzed to [[olmesartan]] during absorption from the gastrointestinal tract. |
* [[Olmesartan medoxomil]] is hydrolyzed to [[olmesartan]] during absorption from the gastrointestinal tract. |
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* [[Mycophenolate mofetil]] is ester of [[mycophenolic acid]] used in transplant medicine. |
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== See also == |
== See also == |
Revision as of 10:42, 2 April 2014
It has been suggested that Active metabolite be merged into this article. (Discuss) Proposed since October 2013. |
A prodrug is a medication that is administered in an inactive or less than fully active form, and then it becomes converted to its active form through a normal metabolic process, such as hydrolysis of an ester form of the drug.
A prodrug is a precursor chemical compound of a drug.[1] Instead of administering a drug, a prodrug might be used instead to improve how a medicine is absorbed, distributed, metabolized, and excreted (ADME).[2][3] 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.
Compound that undergoes biotransformation before exhibiting pharmacological
effects.Note 1: Modified from ref.[4]
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 circulation 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 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 fumarate; note the symbol “ - ” applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies ADEPTs, VDEPs, GDEPs) 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]
Type | Bioactivation site | Subtype | Tissue location of bioactivation | Examples |
---|---|---|---|---|
Type I | Intracellular | Type IA | Therapeutic target tissues/cells | Acyclovir, 5-fluorouracil, cyclophosphamide, diethylstilbestrol diphosphate, |
Type I | Intracellular | Type IB | Metabolic tissues (liver, GI mucosal cell,lung etc.) | Carbamazepine, captopril, carisoprodol, heroin, molsidomine, paliperidone, phenacetin, primidone, psilocybin, sulindac, fursultiamine |
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, bambuterol, chloramphenicol succinate, dihydropyridine pralidoxime, dipivefrin, fosphenytoin |
Type II | Extracellular | Type IIC | Therapeutic Target Tissues/Cells | ADEPTs, GDEPs, VDEPs |
Adapted from Pharmaceuticals (2:77-81, 2009) and Toxicology (236:1-6, 2007).
Examples
- 6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine in vivo.
- 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.
- Enalapril is bioactivated by esterase to the active enalaprilat.
- Valaciclovir is bioactivated by esterase to the active aciclovir.
- Fosamprenavir is hydrolysed to the active amprenavir.
- Levodopa is bioactivated by DOPA decarboxylase to the active dopamine.
- Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol, because pure chloramphenicol does not dissolve in water.
- Psilocybin is dephosphorylated to the active psilocin.
- Heroin is deacetylated by esterase to the active morphine.
- Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide.
- Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone.
- Prednisone, a synthetic cortico-steroid 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.
- Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine.
- Lisdexamfetamine is metabolized in the small intestine to produce dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder
- 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.
- Fesoterodine is an antimuscarinic that is bioactivated to 5-hydroxymethyl tolterodine, the principle active metabolite of tolterodine.
- Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).
- Ximelagatran is dealkylated and dehydroxylated to the active melagatran.
- Codeine is converted to Morphine
- Cyclophosphamide is a prodrug activated by liver cytochrome P450 (CYP) enzymes to form the metabolite 4-hydroxy cyclophosphamide.
- Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase.
- Fenofibrate is an isopropyl ester of fenofibric acid.
- Latanoprost is an isopropyl ester, that is hydrolyzed by esterases in the cornea to the biologically active acid.
- Olmesartan medoxomil is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
- Mycophenolate mofetil is ester of mycophenolic acid used in transplant medicine.
See also
References
- ^ a b c Miles Hacker, William S. Messer II, Kenneth A. Bachmann Pharmacology: Principles and Practice. Academic Press, Jun 19, 2009. pp. 216-217.
- ^ Curr Med Chem. 2009;16(33):4481-9
- ^ 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.
- ^ C. G. Wermuth, C. R. Ganellin, P. Lindberg, L. A. Mitscher (1998). Pure and Applied Chemistry. 70: 1129.
{{cite journal}}
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(help)CS1 maint: multiple names: authors list (link) - ^ "Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)" (PDF). Pure and Applied Chemistry. 84 (2): 377–410. 2012. doi:10.1351/PAC-REC-10-12-04.
- ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11124191, please use {{cite journal}} with
|pmid=11124191
instead. - ^ Karsten Schrör (2009). Acetylsalicylic acid. ISBN 978-3-527-32109-4.
- ^ UK Medicines Information Pharmacists Group. New Medicines on the Market: Desloratidine. June 2001.
- ^ a b c Kuei-Meng Wu. A New Classification of Prodrugs: Regulatory Perspectives Pharmaceuticals 2009, 2, 77-81; <http://dx.doi.org/10.3390/ph2030077>
- ^ Wu, K.M.; Farrelly, J.: Regulatory Perspectives of Type II Prodrug Development and Time-Dependent Toxicity Management: Nonclinical Pharm/Tox Analysis and the Role of Comparative Toxicology" Toxicology 2007, 236, 1–6. <http://dx.doi.org/10.1016/j.tox.2007.04.005>