ADME, Prodrugs, and Excretion - lect 16

Prodrugs

• A prodrug is an inactive compound that is converted into an active drug within the body through metabolic processes or chemical reactions.

• Example: Enalapril (prodrug) is converted to enalaprilat (active drug), improving oral bioavailability.

  • Enalapril has an ester group, making it more lipophilic and allowing it to penetrate cell membranes more readily.

  • Hydrolysis in situ converts enalapril to the active enalaprilat.

Advantages of Prodrugs

• Controlled Release: Prodrugs can provide a controlled release of the active drug, maintaining it within the therapeutic window without frequent dosing.

  • Example: Azathioprine (prodrug) is converted to mercaptopurine (immunosuppressant) under ophthalmic conditions for slow release.

• Masking Toxicity: Prodrugs can mask the toxicity of a compound until it reaches its target site.

  • Example: Cyclophosphamide (prodrug) is non-toxic until it is converted to phosphoramide mustard at the point of action, killing cancer cells.

  • The term "mustard" hints at its relation to toxic nerve agents from the same family as serine.

  • Highlights the risk-benefit balance in drugs where the aim is to kill the pathogen or affected cells before harming the patient.

• Improved Physical-Chemical Properties: Prodrugs can improve the taste or solubility of a drug.

  • Example: Chloramphenicol (antibiotic) has a poor taste and solubility.

    • Prodrugs like chloramphenicol esters (e.g., succinate) are more soluble and can be administered intravenously.

    • Hydrolysis of the ester group releases the active chloramphenicol.

Tapping into Metabolic Pathways

• Prodrugs can be designed to be activated only under specific conditions, tapping into metabolic pathways for targeted action.

  • Example: Methenamine, used for urinary tract infections, is converted to formaldehyde in acidic environments.

    • Infected urinary tracts have a lower pH, causing methenamine to release formaldehyde only when needed.

    • This reduces systemic side effects.

• Fluorouracil:

  • A prodrug where the active drug is built up through metabolic pathways. The drug is related to nucleotide bases and contains a fluorine atom.

    • The fluorine atom is small and can act as an isostere, fooling the body into thinking it's an endogenous base.

    • The body adds it to a ribose or deoxyribose scaffold and phosphorylates it, incorporating it into DNA synthesis.

    • The fluorine atom interferes with hydrogen bonding and molecular recognition, terminating the DNA chain.

    • Targets rapidly multiplying cells, such as cancer cells.

    • Illustrates the race between killing cancer cells and harming healthy cells.

Elimination

• Drugs are eliminated from the body through:

  • Metabolism (e.g., conversion to carbon dioxide).

  • Excretion in urine.

  • Excretion in feces via bile.

  • Elimination through sweat.

Urine Formation

• Occurs in the kidneys, specifically in nephrons (millions per kidney).

• Nephrons are long conduits lined with capillaries.

• Drugs can enter and exit the nephron along its length until they are irreversibly pushed into the urine.

• Processes are:

  • Passive (diffusion).

  • Active (similar to active transport).

• The body aims to retain water and useful molecules while removing waste.

• Unbound drugs (not bound to proteins) are filtered, especially those with a low log P (log P < 0).

• Some compounds are actively secreted.

• Neutral (un-ionized) drugs can undergo passive reabsorption from urine back into the blood.

Solubility

• Solubility is crucial for excretion. Highly lipophilic compounds are excreted readily.

• Polymorphism affects solubility and therapeutic dose.

  • Crystal structure impacts melting point and sweetness, affecting drug delivery and taste.

  • Pharmaceutical companies invest in understanding and controlling polymorphism to optimize drug formulation and protect patents.

  • Essential to verify the crystal structure of toxic drugs to ensure safety.

Improving Solubility

• Functional Groups:

  • Adjusting acidity or basicity can improve solubility.

  • Electron-withdrawing groups increase carboxylic acid acidity (e.g., trifluoroacetic acid).

  • Tweaking functional groups can optimize pKa values to enhance solubility at physiological pH.

  • pKa difference of 5 means one compound is 10^5 times more acidic than the other.

  • Electron-donating groups increase nitrogen base strength.

• Salt Formation:

  • Convert drugs into salts to improve solubility (e.g., cocaine vs. cocaine hydrochloride).

• Encapsulation:

  • Using biological systems or synthetic compounds to encapsulate drugs. Biological systems:

    • Cyclodextrins: Ring of glucose molecules with a hydrophobic pocket for water-insoluble compounds.

    • Liposomes/Vesicles: Synthetic phospholipids that encapsulate drugs for transport.

Formulation

• Converting a drug into a usable form such as tablets, suppositories, etc.

• Key Considerations:

  • Cutting Agents/Bulkers/Fillers: (e.g., chalk, dextrose).

  • Coating Agents: To improve taste.

  • Lubricants: For smooth manufacturing.

  • Preservatives: To prevent oxidation.

  • Antifungal Agents: To prevent microbial contamination.

Summary of ADME

• Metabolism: All drugs undergo metabolism.

  • Phase I: Makes compounds more polar by modifying functional groups.

  • Phase II: Conjugates compounds to water-soluble molecules for excretion.

• Prodrugs: Alter physical chemistry for absorption, mask toxicity, and tap into metabolic pathways.

• High Solubility: Leads to excretion in urine.

• Solubility and Formulation: Critical for drug delivery to the target location.

Research Presentation Notes

• Introduction of Presenter:

  • Itune Collagio works for the Center for Study of Higher Education and Student Success.

  • Both departments are under the Education Directorate at the University of Kent.

  • Encouraged to visit the university website for more information.

• Departments under the Education Directorate:

  • Student Success

  • Center for Study of Higher Education

  • The Library

  • Quality Assurance

  • E-Learning

• Student Success:

  • Organizes programs and events to support academic journeys.

• Center for Study of Higher Education:

  • Relevant for those considering postgraduate studies at Kent.

• Research Project:

  • Representation in chemistry lecture slides: Students' section, reflection, and engagement with subject contents.

  • Focuses on Dr. Piergini's teaching in this module.

  • Collects student reflections to improve learning for chemistry students.

• Research Methods:

  • Focus group (60 minutes, £10 on Kent card, snacks provided).

  • A one-time survey administration.

• Study Personnel:

  • Principal Investigator: Itune Collagio.

  • Working alongside Dr. Biagini and Professor Catherine Quinlan.

  • Professor Quinlan is the center director for the Center for Study of Higher Education.

• Invitation and Incentives:

  • Students are invited to a focus group lasting 60 minutes.

  • Offered £10 on their Kent card and snacks during the session.

• Risks:

  • Discussions on race and discrimination, which may be sensitive and emotionally challenging.

• Steps to Mitigate Risks:

  • Participation is voluntary.

  • Participants can step away from the conversation.

  • Participants can skip any question or discontinue the conversation.

  • Participants can withdraw from the study within one month of starting.

• Benefits:

  • Opportunity to reflect on the curriculum and engage with the course content.

• Confidentiality:

  • Comments remain anonymous and will not be shared with the lecturer.

• Questions Encouraged:

  • Participants are invited to ask any questions about the project.

Prodrugs

• A prodrug is an inactive compound that is converted into an active drug within the body through metabolic processes or chemical reactions. The conversion can occur through enzymatic reactions, hydrolysis, or other chemical transformations.

• Example: Enalapril (prodrug) is converted to enalaprilat (active drug), improving oral bioavailability.

  • Enalapril has an ester group, making it more lipophilic, which enhances its ability to penetrate cell membranes more readily.

  • Hydrolysis in situ converts enalapril to the active enalaprilat, which is an ACE inhibitor used to treat hypertension.

Advantages of Prodrugs

• Controlled Release: Prodrugs can provide a controlled release of the active drug, maintaining it within the therapeutic window without frequent dosing. This can be achieved through various chemical modifications that affect the rate of conversion to the active drug.

  • Example: Azathioprine (prodrug) is converted to mercaptopurine (immunosuppressant) under ophthalmic conditions for slow release. This approach minimizes systemic exposure while providing local therapeutic effects.

• Masking Toxicity: Prodrugs can mask the toxicity of a compound until it reaches its target site. This strategy can improve the therapeutic index of a drug by reducing off-target effects.

  • Example: Cyclophosphamide (prodrug) is non-toxic until it is converted to phosphoramide mustard at the point of action, killing cancer cells. This conversion primarily occurs in cancer cells due to their specific enzymatic activities.

    • The term "mustard" hints at its relation to toxic nerve agents from the same family as serine, reflecting the compound's potent cytotoxic properties.

    • Highlights the risk-benefit balance in drugs where the aim is to kill the pathogen or affected cells before harming the patient. The goal is to maximize the drug's effect on diseased cells while minimizing harm to healthy tissues.

• Improved Physical-Chemical Properties: Prodrugs can improve the taste or solubility of a drug, making it easier to administer. For instance, they can enhance oral absorption or allow for intravenous administration.

  • Example: Chloramphenicol (antibiotic) has a poor taste and solubility, making it challenging to administer, particularly in pediatric formulations.

  • Prodrugs like chloramphenicol esters (e.g., succinate) are more soluble and can be administered intravenously, bypassing the taste issue and improving drug delivery.

    • Hydrolysis of the ester group releases the active chloramphenicol, ensuring the drug's therapeutic effect is achieved.

Tapping into Metabolic Pathways

• Prodrugs can be designed to be activated only under specific conditions, tapping into metabolic pathways for targeted action. This approach enhances drug selectivity and reduces systemic side effects.

  • Example: Methenamine, used for urinary tract infections, is converted to formaldehyde in acidic environments, providing a localized antimicrobial effect.

    • Infected urinary tracts have a lower pH, causing methenamine to release formaldehyde only when needed, thereby reducing systemic side effects.

• Fluorouracil:

  • A prodrug where the active drug is built up through metabolic pathways. The drug is related to nucleotide bases and contains a fluorine atom, which interferes with DNA synthesis.

  • The fluorine atom is small and can act as an isostere, fooling the body into thinking it's an endogenous base, allowing it to be processed by cellular enzymes.

    • The body adds it to a ribose or deoxyribose scaffold and phosphorylates it, incorporating it into DNA synthesis. This incorporation disrupts the normal DNA replication process.

    • The fluorine atom interferes with hydrogen bonding and molecular recognition, terminating the DNA chain, thus preventing cell division.

    • Targets rapidly multiplying cells, such as cancer cells, making it an effective chemotherapy agent.

    • Illustrates the race between killing cancer cells and harming healthy cells, highlighting the challenges in cancer therapy to minimize damage to healthy tissues.

Elimination

• Drugs are eliminated from the body through various routes to terminate their action and prevent accumulation. These routes include:

  • Metabolism (e.g., conversion to carbon dioxide), where drugs are chemically altered to facilitate their removal.

  • Excretion in urine, where water-soluble metabolites and unchanged drugs are filtered by the kidneys.

  • Excretion in feces via bile, a pathway for larger molecules and metabolites to be eliminated through the digestive system.

  • Elimination through sweat, a minor route for some drugs.

Urine Formation

• Occurs in the kidneys, specifically in nephrons, which are the functional units of the kidney (millions per kidney). Each nephron contributes to filtering blood and forming urine.

• Nephrons are long conduits lined with capillaries, facilitating the exchange of substances between the blood and the forming urine.

• Drugs can enter and exit the nephron along its length until they are irreversibly pushed into the urine. This process involves several mechanisms:

  • Passive (diffusion), where drugs move across membranes from areas of high concentration to low concentration.

  • Active (similar to active transport), where drugs are transported by specific carrier proteins, often requiring energy.

• The body aims to retain water and useful molecules while removing waste, ensuring essential substances are not lost during urine formation.

• Unbound drugs (not bound to proteins) are filtered, especially those with a low log P (log P < 0), making them more water-soluble and easier to excrete.

• Some compounds are actively secreted, allowing the body to efficiently remove specific substances from the blood into the urine.

• Neutral (un-ionized) drugs can undergo passive reabsorption from urine back into the blood, affecting the overall excretion rate of the drug.

Solubility

• Solubility is crucial for excretion, influencing how readily a drug can be eliminated from the body. Highly water-soluble compounds are excreted more efficiently.

• Polymorphism affects solubility and therapeutic dose. Different crystal structures can significantly alter a drug's bioavailability and efficacy.

  • Crystal structure impacts melting point and sweetness, affecting drug delivery and taste. These factors can influence patient compliance and drug formulation.

  • Pharmaceutical companies invest in understanding and controlling polymorphism to optimize drug formulation and protect patents. Ensuring consistent drug performance and safeguarding intellectual property are key considerations.

  • Essential to verify the crystal structure of toxic drugs to ensure safety, as different polymorphs can have varying toxicity profiles.

Improving Solubility

• Functional Groups:

  • Adjusting acidity or basicity can improve solubility, allowing drugs to dissolve more readily in physiological environments.

  • Electron-withdrawing groups increase carboxylic acid acidity (e.g., trifluoroacetic acid), enhancing its ionization and solubility.

  • Tweaking functional groups can optimize pKa values to enhance solubility at physiological pH, ensuring the drug is in its most soluble form under biological conditions.

  • pKa difference of 5 means one compound is 10^5 times more acidic than the other, significantly impacting its solubility and ionization.

  • Electron-donating groups increase nitrogen base strength, affecting its ability to form salts and dissolve in aqueous solutions.

• Salt Formation:

  • Convert drugs into salts to improve solubility (e.g., cocaine vs. cocaine hydrochloride), making them more suitable for various formulations.

• Encapsulation:

  • Using biological systems or synthetic compounds to encapsulate drugs, protecting them and enhancing their solubility.

  • Biological systems:

    • Cyclodextrins: Ring of glucose molecules with a hydrophobic pocket for water-insoluble compounds, allowing them to dissolve more easily in aqueous solutions.

    • Liposomes/Vesicles: Synthetic phospholipids that encapsulate drugs for transport, improving their bioavailability and targeted delivery.

Formulation

• Converting a drug into a usable form such as tablets, suppositories, etc., ensuring it can be administered effectively and safely.

• Key Considerations:

  • Cutting Agents/Bulkers/Fillers: (e.g., chalk, dextrose) to increase the size and stability of the formulation.

  • Coating Agents: To improve taste, mask odors, and control the release of the drug.

  • Lubricants: For smooth manufacturing, preventing the drug from sticking to equipment.

  • Preservatives: To prevent oxidation and maintain the drug's integrity over its shelf life.

  • Antifungal Agents: To prevent microbial contamination, ensuring the drug remains safe for consumption.

Summary of ADME

• Metabolism: All drugs undergo metabolism to varying degrees, influencing their activity and duration in the body.

  • Phase I: Makes compounds more polar by modifying functional groups, preparing them for Phase II reactions.

  • Phase II: Conjugates compounds to water-soluble molecules for excretion, facilitating their elimination from the body.

• Prodrugs: Alter physical chemistry for absorption, mask toxicity, and tap into metabolic pathways, enhancing drug efficacy and safety.

• High Solubility: Leads to excretion in urine, preventing the drug from accumulating in the body.

• Solubility and Formulation: Critical for drug delivery to the target location, ensuring the drug reaches its intended site of action.

Research Presentation Notes

• Introduction of Presenter:

  • Itune Collagio works for the Center for Study of Higher Education and Student Success, focusing on improving student outcomes.

  • Both departments are under the Education Directorate at the University of Kent, working collaboratively to enhance the educational experience.

  • Encouraged to visit the university website for more information, providing resources for further learning and engagement.

• Departments under the Education Directorate:

  • Student Success, dedicated to supporting students' academic and personal growth.

  • Center for Study of Higher Education, conducting research to inform and improve higher education practices.

  • The Library, providing access to resources and support for learning and research.

  • Quality Assurance, ensuring the standards of education are maintained and improved.

  • E-Learning, facilitating the use of technology to enhance teaching and learning.

• Student Success:

  • Organizes programs and events to support academic journeys, fostering a positive and inclusive learning environment.

• Center for Study of Higher Education:

  • Relevant for those considering postgraduate studies at Kent, offering opportunities for advanced research and learning.

• Research Project:

  • Representation in chemistry lecture slides: Students' section, reflection, and engagement with subject contents, aiming to understand and improve student experiences.

  • Focuses on Dr. Piergini's teaching in this module, providing insights into effective chemistry education.

  • Collects student reflections to improve learning for chemistry students, ensuring the course content is relevant and engaging.

• Research Methods:

  • Focus group (60 minutes, £10 on Kent card, snacks provided), allowing for in-depth qualitative data collection.

  • A one-time survey administration, gathering quantitative data to support the findings from the focus groups.

• Study Personnel:

  • Principal Investigator: Itune Collagio, leading the research project.

  • Working alongside Dr. Biagini and Professor Catherine Quinlan, bringing expertise in chemistry education and research.

  • Professor Quinlan is the center director for the Center for Study of Higher Education, providing guidance and support for the project.

• Invitation and Incentives:

  • Students are invited to a focus group lasting 60 minutes, providing a platform for open and honest feedback.

  • Offered £10 on their Kent card and snacks during the session, incentivizing participation and showing appreciation for their time.

• Risks:

  • Discussions on race and discrimination, which may be sensitive and emotionally challenging, requiring careful facilitation.

• Steps to Mitigate Risks:

  • Participation is voluntary, ensuring students are not pressured to participate.

  • Participants can step away from the conversation, allowing them to withdraw if they feel uncomfortable.

  • Participants can skip any question or discontinue the conversation, giving them control over their involvement.

  • Participants can withdraw from the study within one month of starting, providing a period for reflection and reconsideration.

• Benefits:

  • Opportunity to reflect on the curriculum and engage with the course content, fostering a deeper understanding and appreciation.

• Confidentiality:

  • Comments remain anonymous and will not be shared with the lecturer, encouraging honest and open feedback.

• Questions Encouraged:

  • Participants are invited to ask any questions about the project, ensuring they are fully informed and engaged