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Prodrugs — Properties and Applications

Prodrugs are derivatives of drug molecules that can undergo an enzymatic and/or chemical transformation Transformation Change brought about to an organism's genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell's genome. Bacteriology in vivo to release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology the active drug. Prodrugs are incorporated to improve the physicochemical, pharmacokinetic and pharmacodynamic properties of compounds. In this article, the concept of prodrugs and its properties is discussed. Emphasis is given to the different applications where prodrugs may be applied.

Last updated: 8 Mar, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Prodrug

The prodrug Prodrug Nitroimidazoles was defined first by Adrien Albert in 1958 to refer to the pharmacologically inactive compound that is transformed into an active substance when it reacts or is metabolized in mammalian systems. Incorporation of a prodrug Prodrug Nitroimidazoles allows a delay in the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of the active drug.  It also helps in overcoming some common problems in drug formulations which include chemical instability, inadequate brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification penetration Penetration X-rays, poor aqueous solubility, local irritation and toxicity Toxicity Dosage Calculation, and insufficient oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.

A prodrug Prodrug Nitroimidazoles is formally defined as a biologically inactive derivative of a parent drug molecule, which is activated by a chemical or enzymatic transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology within the body, which, in the process, involves the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of the active drug. They usually possess improved delivery properties compared to the parent molecule. This includes improved lipophilicity and the addition of structural features that enable improved drug targeting. The physicochemical, biopharmaceutical and pharmacokinetic properties of drugs are also enhanced, increasing the usefulness of the drug.

The use of a prodrug Prodrug Nitroimidazoles is to optimize the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption, distribution, metabolism, excretion and unwanted toxicity Toxicity Dosage Calculation of the parent drug. There are three basic objectives in prodrug Prodrug Nitroimidazoles research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest: Pharmaceutical, pharmacokinetic and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics. For the pharmaceutical objective, prodrug Prodrug Nitroimidazoles research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest aims to improve solubility, chemical stability and other chemical properties of drugs, decreasing occurrences of irritation and pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways after drug administration.

For the pharmacokinetic objectives, prodrug Prodrug Nitroimidazoles research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest aims to improve drug absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption and decreasing pre-systemic metabolism. The time profiles are also improved and increase organ/tissue-selective delivery of the active agent. For the pharmacodynamic activity, prodrug Prodrug Nitroimidazoles research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest also aims to decrease the toxicity Toxicity Dosage Calculation and improve the therapeutic index Therapeutic Index An indicator of the benefits and risks of treatment. Dosage Calculation of drugs.

Increased Aqueous Solubility

Since bodily systems rely mainly on water as the solvent, aqueous solubility is important in studying the drug properties. Some drugs need improvement in their aqueous solubility to increase their viability. One way to achieve this is by incorporating esters and amide groups which involve improving the ionic nature of the drug increasing its aqueous solubility. An example of this prodrug Prodrug Nitroimidazoles is Valacyclovir Valacyclovir A prodrug of acyclovir that is used in the treatment of herpes zoster and herpes simplex virus infection of the skin and mucous membranes, including genital herpes. Herpes Zoster (Shingles) which are esters of the antiviral Antiviral Antivirals for Hepatitis B drug Acyclovir Acyclovir A guanosine analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Herpes Zoster (Shingles).

Increased Lipophilicity

In general, most of the drugs should be relatively lipophilic to enable faster transport of active molecules through the biological membranes. The need to improve the lipophilicity of the drug is for compounds containing polar or ionizable groups. This is achieved by the preparation of ester prodrugs. An example of such prodrug Prodrug Nitroimidazoles is Ketorolac which is a non-steroidal anti-inflammatory drug with analgesic activity. Another example is Famciclovir Famciclovir An aminopurine derivative and prodrug of penciclovir which is a competitive inhibitor of herpes simplex 2 DNA polymerase. It is used to treat herpes simplex virus infection. Antivirals for Herpes Virus ( prodrug Prodrug Nitroimidazoles of Penciclovir Penciclovir Antivirals for Herpes Virus):

Prodrug1 625x209 1

Improved Targetability

Some diseases require a drug to be released from the target tissue or organ systems. This is needed to reduce the risk of unwanted exposure Exposure ABCDE Assessment of the non-target tissues from some undesirable effects of the drugs.

Prodrugs enable a more targeted mechanism for drug actions reducing toxicity Toxicity Dosage Calculation risks. The use of chemotherapeutic drugs involves very high toxic effects on normal and cancer cells. Because of this, there is a great need for prodrugs here so as to prevent the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of the active drug before reaching the target site. An example of an anticancer prodrug Prodrug Nitroimidazoles is Capecitabine Capecitabine A deoxycytidine derivative and fluorouracil prodrug that is used as an antineoplastic antimetabolite in the treatment of colon cancer; breast cancer and gastric cancer. Antimetabolite Chemotherapy, which is a triple prodrug Prodrug Nitroimidazoles of 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy. With the employment of triple prodrug Prodrug Nitroimidazoles, the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of the drug is delayed, improving the targetability of the drug.

Some other types of prodrugs that can improve targetability are enzyme-activated prodrugs; targeting-ligand conjugated prodrug Prodrug Nitroimidazoles, enzyme-cleavable prodrug Prodrug Nitroimidazoles, membrane transporter-associated prodrug Prodrug Nitroimidazoles, and polymeric prodrug Prodrug Nitroimidazoles.

For tumor-ligand conjugated prodrug Prodrug Nitroimidazoles, a tumor-specific monoclonal antibody is attached to the oncostatin drugs. When the antibody is delivered to the site of cancer, receptor-mediated pinocytosis Pinocytosis The engulfing of liquids by cells by a process of invagination and closure of the cell membrane to form fluid-filled vacuoles. Pharmacokinetics and Pharmacodynamics occurs releasing the active compound.

Prolonged Duration of Action

Incorporation of prodrugs also finds importance in prolonging the duration of drug action. This is because most drugs only have very short half-lives that are why frequent dosing is required. What is not good with conventional drug formulation is that it involves the sudden peaking of the drug concentration in the body, which may not be good for most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
One way to aid this is by incorporating a prodrug Prodrug Nitroimidazoles that enables releasing of the active drug in longer periods of time and only enough drugs that will exhibit therapeutic effect will be released over longer periods of time. Another way is to modify the parent in such a way that the prodrug Prodrug Nitroimidazoles will take some time for the conversion, enabling the drug action to last longer. This approach is extremely useful in avoiding large fluctuations of the drug concentration in the blood plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products. An example of this prodrug Prodrug Nitroimidazoles is the hemisuccinate prodrug Prodrug Nitroimidazoles of Propranolol Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs. Antiadrenergic Drugs.

References

  1. Zawilska, J., Wojciezak, J., & Olejniczak, A. Prodrugs: A challenge for the drug development. Pharmacological Reports. 2013. Institute of Pharmacology Polish Academy of Science.
  2. Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Jarvinen, T., & Savolainen, J. Prodrugs: Design and Clinical Applications. Nature Reviews Drug Discovery 7, 255-270 (February 2008)

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