Prodrug

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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.

Contents
[hide]
• 1 Classification
• 2 Examples
• 3 See also
• 4 References
• 5 External links

[edit] 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.[1][2]
Table 1: Classification of prodrugs
Bioactivation Tissue location of
Type Subtype Examples
site bioactivation
Acyclovir, 5-Flurouracil,
Cyclophosphamide, Diethylstilbestrol
Type Therapeutic target diphosphate,
Intracellular Type IA
I tissues/cells
L-Dopa, 6-Mercaptopurine,
Mitomycine C, Zidovudine
Carbamazepine, Captopril,
Metabolic tissues Carisoprodol, Heroin, Molsidomine,
Type
Intracellular Type IB (liver, GI mucosal Paliperidone, Phenacetin, Primidone,
I
cell,lung etc) Psilocybin, Suldinac,
Tetrahydrofurfuryl disulfide
Type Type Lisdexamfetamine, Loperamide oxide,
Extracellular GI fluids
II IIA Oxyphenisatin, Sulfasalazine
Acetylsalicylate, Bacampicillin,
Systemic circulation Bambuterol, Chloramphenicol
Type and Other succinate,
Extracellular Type IIB
II Extracellular Fluid
Dihydropyridine pralixoxime,
Compartments
Dipivefrin, Fosphenytoin
Type Therapeutic Target
Extracellular Type IIC ADEPTs, GDEPs, VDEPs
II Tissues/Cells
Adapted from Pharmaceuticals (2:77-81, 2009) and Toxicology (236:1-6, 2007).
[edit] Examples
• Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active
morphine in vivo.
• Carisoprodol is metabolized into meprobamate. Carisoprodol is not a controlled
substance in the United States, but meprobamate is 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.
• Valacyclovir is bioactivated by esterase to the active acyclovir.
• 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 tolterodine.
• Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated
to tenofovir (PMPA).
[edit] See also
• Toxification
[edit] References
1. ^ see Table 1; Wu,K.M.: A New Classification of Prodrugs: Regulatory Perspectives
Pharmaceuticals 2:77-81, 2009.<http://dx.doi.org/10.3390/ph2030077>.
2. ^ see Table 1; 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>

[edit] External links

• Special Issue on Prodrugs: from Design to Applications
Retrieved from "http://en.wikipedia.org/wiki/Prodrug"
Categories: Pharmacology | Prodrugs
Hidden categories: Articles needing additional references from January 2008 | All articles
needing additional references
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