Structural Biochemistry/Prodrugs

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Prodrugs are a new class of drugs that, upon administration, are inactive. Upon absorption, the drug becomes activated. This process, called bioactivation, occurs by in vivo metabolism. Prodrugs are useful in that they can be used to avoid negative physiological effects associated with the absorption of standard drugs.[1] The potential benefits of this class of drugs are vast. They provide improved drug targeting, and higher concentration of active ingredients where needed. Problems of standard drugs that could potentially be overcome by the use of prodrugs include insufficient absorption when absorbed orally, limited solubility, and irritation associated with administration.[2]

Undesirable Properties[edit | edit source]

- Physical Properties: Poor aqueous solubility, low lipophilicity and chemical instability - Pharmacokinetic Properties: Poor distribution across biological membranes, good substrate for first-pass metabolism, rapid absorption/excretion when long-term effect desired.

Classification of Prodrugs[edit | edit source]

Looking on how the human body converts the prodrug into the final active drug form, there are actually two major types of prodrugs.

One type of prodrug is called the Type I prodrugs. This type of prodrug is bioactivated intracellularly. Lipid-lowering statins and anti-viral nucleoside analogs are both examples of Type I prodrugs. There is another prodrug called the Type II prodrugs. Unlike that of Type I prodrug, Type II prodrugs are bioactivated extracellularly, especially in the body's circulation system or the digestive fluids. For example, antibody, or virus-directed enzyme are all types of Type II prodrug. These are also commonly used in immunotherapy or chemotherapy.

Subtypes of Prodrugs[edit | edit source]

It is also seen that Type I and Type II prodrugs can be categorized into Subtypes. For example, Type I has a bioactivation site that is intracellular and it contains subtype of Type IA and Type IB. Type IA is often located in the therapeutic target tissues or cells. Example of this can be diethlstilbestrol diphosphate or 6-mercaptopurine. Then there is Type IB where is located in the metabolic tissues of the liver, Gl mucosal cell, or the lungs and examples for this subtype can be that of heroin, primidone, or captopril.

Furthermore, just like how Type I can be classified into different Subtypes, Type II prodrugs also do the same thing. For instance, Type II has a bioactivation site that is extracellular and it contains subtype of Type IIA, Type IIB, and Type IIC. Type IIA is usually found in the GI fliuds and example of this can be sulfasalazine. Type IIB is found in the systemic circulation and other extracellular fluid compartments. Chloramphenicol succinate or dipivefrin are examples of Type IIB prodrugs. Last but not least, Type IIC such as those of ADEPTs, VDEPs, or GDEPs is all found in the therapeutic target tissues or cells.

Thus, there are different types and kinds of prodrugs because one type of prodrugs contains couple or several subtypes that are typically found in different locations of the body.

Steps in Prodrug Design[edit | edit source]

- Identification of drug delivery problem and identification of desired physicochemical properties - Selection of transport moiety which will give prodrug desired transport properties and be readily cleaved in the desired biological compartment

Design and Structure[edit | edit source]

Currently, many prodrugs employ primarily hydroxyl, amine, and carboxyl groups. Esters are found most commonly in commercial prodrugs, such as the drug oseltamivir. More atypical groups have also been investigated for use in prodrugs, such as thiols and imines.[3] The bioconversion of the prodrugs to their active parent drugs is by way of enzyme activity of hydrolases. Prodrugs can be designed to bioconvert based upon the specific characteristics of the enzymes that catalyze the reaction, specifically substrate recognition. [4]

Examples[edit | edit source]

The prodrug Famvir has recently been developed in an attempt to prevent the spread of three different types of the herpes simplex virus: type 1, type 2, and the varicella zoster virus. This drug contains two ester groups and requires two enzymes to bioconvert the molecule into its active form, which takes place predominantly in the liver.

Hepsera (Adefovir dipivoxil), another diester prodrug, is responsible for inhibiting nucleoside reverse transcriptase against the hepatitis B virus. Absorption of this drug occurs orally and at a very rapid pace, with maximum absorption occurring after just 3/4 of an hour.

Viread is a carbonate-based prodrug, as opposed to the ester-based prodrugs mentioned previously. Its purpose is to inhibit the nucleoside transcriptase in the HI virus and the hepatitis B virus. The carbonate group contained in this prodrug has been found to be more stable than the ester groups contained in the aforementioned prodrugs, while maximum absorption is reached more slowly.

References[edit | edit source]

  4. Imai, Teruko, and Masakiyo Hosokawa. "Prodrug Approach Using Carboxylesterases Activity: Catalytic Properties And Gene Regulation Of Carboxylesterase In Mammalian Tissue." Journal Of Pesticide Science 35.3 (2010): 229-239.