Prodrug

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A prodrug is a medication that is administered in an inactive or less than fully active form, and is then 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.

IUPAC definition

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[edit]

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Terfenadine, the first non-sedating antihistamine, had to be withdrawn from the market because of the small risk of a serious side effect.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[edit]

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 Table 1 below for further subtype categorization.[9]

Subtypes[edit]

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]

Table 1: Classification of prodrugs
Type Bioactivation site Subtype Tissue location of bioactivation Examples
Type I Intracellular Type IA Therapeutic target tissues/cells Acyclovir, 5-fluorouracil, cyclophosphamide, diethylstilbestrol diphosphate,

L-dopa, 6-mercaptopurine, mitomycin C, zidovudine

Type IB Metabolic tissues (liver, GI mucosal cell,lung etc.) Carbamazepine, captopril, carisoprodol, heroin, molsidomine, 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, dihydropyridine pralidoxime, dipivefrin, fosphenytoin, Lisdexamfetamine
Type IIC Therapeutic Target Tissues/Cells ADEPTs, GDEPs, VDEPs

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

Examples[edit]

See also[edit]

References[edit]

  1. ^ a b c Miles Hacker, William S. Messer II, Kenneth A. Bachmann Pharmacology: Principles and Practice. Academic Press, Jun 19, 2009. pp. 216-217.
  2. ^ Curr Med Chem. 2009;16(33):4481-9
  3. ^ 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. 
  4. ^ C. G. Wermuth, C. R. Ganellin, P. Lindberg, L. A. Mitscher (1998). Pure and Applied Chemistry 70: 1129. doi:10.1351/pac199870051129. 
  5. ^ "Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)". Pure and Applied Chemistry 84 (2): 377–410. 2012. 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.  edit
  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. ^ 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>
  10. ^ 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>

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