prodrug

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A prodrug is a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into an active metabolite. 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 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. Sometimes the use of a prodrug is unintentional, however, especially in the case of serendipitous drug discoveries, and the drug is only identified as a prodrug after extensive drug metabolism studies.

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.^[1]

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).

Examples

• 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 converted by esterase to the active enalaprilat.
• Valacyclovir is converted by esterase to the active acyclovir.
• Fosamprenavir is hydrolysed to the active amprenavir.
• Levodopa is converted 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.
• Codeine is demethylated by the liver enzyme CYP2D6 to the active morphine, as well as several other compounds that may be active in analgesia.
• Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide.
• Paliperidone (Invega) is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone (Risperdal).
• Prednisone, a synthetic cortico-steroid drug, is converted 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 converted 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.

See also

• Toxification

References

External links

• Special Issue on Prodrugs: from Design to Applications