Prodrug

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A prodrug is a pharmacological substance (drug) which is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into the active compound.

Rationale for Development

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, often due to the chemical properties of the drug.

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 convert 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 chemical properties likely to improve absorption and the major metabolic pathways in the body allows the modification of the structure of new chemical entities for improved bioavailability.

However, sometimes the use of a prodrug is unintentional, especially in the case of serendipitous drug discoveries, and the drug is only identified as a prodrug after extensive drug metabolism studies. Some prodrugs, such as Codeine and Psilocybin, also occur naturally.

Classification

Prodrugs can be classified into two types based on their sites of conversion into the final active drug form: Type I, those that are converted intracellularly (e.g., anti-viral nucleoside analogs, lipid-lowering statins, antibody-directed/gene-directed enzyme prodrugs [ADEP/GDEP] for chemotherapy), and Type II, those that are converted extracellularly, especially in digestive fluids or the systemic circulation (e.g., etoposide phosphate, valganciclovir, fosamprenavir). Both types can be further categorized into subtype A or B, based on additional criteria. Those for the Type IA and IB are whether or not the cellular converting location is the site of therapeutic action. For the Type IIA and IIB, they are categorized depending on whether the conversion occurs in the gastrointestinal (GI) fluids or systemic circulation (see Table 1; Wu and Farrelly, Toxicology 236:1-6, 2007).

Table 1: Classification of prodrugs

Type	Converting site	Subtype	Tissue location of conversion	Examples
Type I	Intracellular	Type IA	Therapeutic target tissues/cells	Zidovudine, 5-Flurouracil
Type I	Intracellular	Type IB	Metabolic tissues (liver/lung etc)	Captopril, Cyclophosphamide
Type II	Extracellular	Type IIA	GI fluid	Sulfasalazine, Loperamide oxide
Type II	Extracellular	Type IIB	Systemic circulation	Fosphenytoin, Bambuterol

A prodrug can belong to both a Type IA and IB category when the site of the therapeutic target and conversion are the same (e.g., HMG Co-A reductase inhibitors).

Selected examples

• Enalapril is converted by esterase to the active enalaprilat.
• Valaciclovir is converted by esterase to the active aciclovir.
• Levodopa is converted by DOPA decarboxylase to the active dopamine.
• Chloramphenicol succinate ester is used as 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.
• Codeine is demethylated by the liver enzyme CYP2D6 to the active morphine, as well as several other compounds that may be active in analgesia.
• gamma-Butyrolactone (GBL) is condensed (lactonized) form of gamma-Hydroxybutyric acid (GHB)

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