Prodrugs Concept & Applications

Prodrugs Concept & Applications

• Prodrugs are compounds designed for pharmacological activity but not susceptible to metabolic or chemical transformation until the body acts upon them.
• Hard drugs are compounds with structural characteristics necessary for activity but do not require transformation to be active.
• Prodrugs increase metabolic efficiency by avoiding metabolism initially, resulting in no toxic metabolites.
• However, prodrugs are less readily eliminated because metabolism is avoided.
• Two mechanisms for prodrug activation: enzymatic and chemical.
• Enzymatic conversion is more common, and is chemically stable degradation within the body and is patient dependent.
• Chemical conversion is less common, chemically unstable, occurs outside the body, and is not patient dependent.

Types of Prodrugs

• Prodrugs contain various compounds with different functional groups.
• Prodrugs can include esters, amides, imides, amines, and compounds with carbonyl groups.
• Ester prodrugs easily synthesized if molecule has an alcohol or carboxylic acid.
• Examples of prodrug types include esters, amides, and imides.
• Esters are compounds with an ester group.
• Amides include primary, secondary, and tertiary amine groups.
• Imides have nitrogen double bonds.

Functional Groups in Prodrugs

• Carboxylic acids and alcohols are most common.
• Includes types of esterase enzymes such as ester hydrolase and related enzymes.
• Wide variety of alcohol promoieties available.
• Steric, electronic, and hydrophobicity properties control the rate and extent of hydrolysis.
• Examples include Erythromycin, an antibiotic useful in treating respiratory infections, Legionnaires' disease, and skin infections.

Examples of Prodrugs

• Chloramphenicol(antibiotic) is given parentrally by IM inj.
• It is painful since it precipitates at the injection site due to low water solubility.
• Enhancing water solubility using a polar functional group, like succinate, reduces pain.
• Prodrugs' design often involves increasing lipid solubility or changing pH stability to improve absorption or resistance to degradation in the body or outside of the body.

β-Lactam prodrug – Double Esters

• Increased absorption and less acid decomposition are the goals for these prodrugs.
• They are useful for treating upper and lower respiratory diseases, Legionnaire's disease, skin infections.

Other Ester Prodrugs - Soluble

• Sodium succinate prodrugs are unstable and should be used immediately.
• They are more stable with less tendency towards hydrolysis.
• Sulfate and phosphate prodrugs also exist.

Example of increasing absorption by addition of a nonpolar carboxylic acid

• Polar functional groups increase solubility and reduce pain with injection as in chloramphenicol.
• This technique is applied to increase drug absorption and improve its clinical efficacy.
• Pivalic acid has demonstrated effectiveness for increasing epinephrine absorption.

Example (Double ester prodrug)

• Cefpodoxime proxetil and cefuroxime axetil are double ester prodrugs, designed for increased water solubility for better absorption.
• They are unstable forms of the parent active drug.

Example (Mutual prodrug)

• Estramustine is a prodrug combining normustard, an alkylating agent, with estradiol. This is intended for prostatic cancer treatment, using the synergistic effect of both compounds.
• The drug is administered as an inactive form by a drug carrier, which must release the drug for it to act.

Prodrugs for Stability (first-pass metabolism)

• Prodrugs are used to improve drug stability and reduce metabolism or breakdown in the body.
• They are especially important for drugs that are rapidly metabolized when first entering and are absorbed into the bloodstream.

2-Amines

• Amides are less commonly used as prodrugs because of high chemical stability.
• Lack of amidase enzymes for hydrolysis is a challenge for amide prodrugs.
• Activated amides that typically are low-basicity amines, or amides of amino acids, are more likely to be cleaved enzymatically.
• N-Mannich bases are used to lower the pKa of amines.

4. Human eye

• Lipophilic esters show better corneal penetration.
• The more polar form of the drug, epinephrine, is readily available and active in the eye, so it performs better as an antiglaucoma prodrug.

4. Colon and lower GI tract

• Colon bacteria demonstrate increased effectiveness when glycoside derivatives are administered.
• Polar glycoside derivatives have poor absorption, allowing them to act as substrates for colon bacteria which are prevalent in the human colon.

Antitumor agent

• High growth rates in tumor tissue increase enzyme activities such as peptidases and proteases. These cells are better targets for anticancer prodrugs.
• Capecitabine is a prodrug used to treat cancer. It is a carbamic acid that converts into 5-deoxy-5-fluorocytidine and then 5-deoxy-5-fluorouridine. The latter is a precursor to the active drug fluorouracil which acts more selectively on tumor cells.

Chemical Delivery Systems

• Many delivery systems use oxidative, reductive, or phosphorylation activation processes to release the drug.
• Examples include drugs which involve bioprecursor prodrugs that are chemically activated in the body to produce the active drug form.
• Pro-2-PAM is used to treat enzyme inhibitors in insecticides or nerve agents, since it easily crosses the blood-brain barrier (BBB).

Tripartate Prodrugs

• These prodrug systems use a carrier to help transport the drug to the target. They are often more effective in targeting specific sites.
• The linkage between carrier and drug is more stable to prevent degradation during administration to the site of delivery.

Macro-molecular Drug Carriers

• These may be superior to short prodrugs in how well they target a particular receptor site.
• These carriers increase the stability and bioavailability of drugs to help them reach their target.