Drug Metabolism
TLDRThis lecture delves into the intricate world of drug metabolism, emphasizing its critical role in the body's detoxification process. The primary function of drug metabolism is to facilitate the removal of drug molecules, achieved by modifying these molecules through the addition of functional groups. The process is bifurcated into Phase I and Phase II, with Phase I focusing on making the drug more water-soluble through oxidation, reduction, and hydrolysis, and Phase II involving conjugation reactions that further enhance water solubility. The lecture highlights the importance of understanding the cytochrome P450 system, a group of enzymes pivotal in the oxidation process. It also touches upon factors influencing drug metabolism, such as age, genetics, and the route of drug administration. The speaker illustrates various metabolic transformations with examples like phenopropan, tolbutamine, and codeine, and discusses the formation of potentially toxic metabolites. The summary underscores the complexity of drug metabolism, the significance of enzyme involvement, and the body's efficient approach to metabolize and excrete xenobiotics, ensuring the safety and efficacy of drug therapies.
Takeaways
- 🌟 The primary purpose of drug metabolism is to enhance the removal of drug molecules from the body by making them more water-soluble.
- 🔄 Drug metabolism can either activate pro-drugs into more active compounds, inactivate drugs, or detoxify toxic compounds.
- 🧬 The liver is the major site of drug metabolism, but other organs like the GI tract, kidneys, lungs, and even the skin can participate.
- 👶 Age, genetic polymorphism, and the route of drug administration are practical considerations that can affect how a drug is metabolized.
- 🍃 Phase I metabolism involves oxidation, reduction, and hydrolysis to make the molecule more polar, while Phase II involves conjugation reactions that add endogenous molecules for further water solubility.
- 🌡 The physical chemical properties of a drug, such as being hydrophilic or hydrophobic, influence the extent of its metabolism.
- 🧬 Cytochrome P450 enzymes are crucial in Phase I metabolism, oxidizing specific positions of molecules like cholesterol.
- 💊 Factors such as steric hindrance and the presence of electron-donating or withdrawing groups on aromatic rings can affect the site of oxidation.
- ⚠️ Aromatic ring hydroxylation can lead to the formation of reactive intermediates like epoxides, which can be toxic unless detoxified by molecules like glutathione.
- 🔄 Multiple metabolic pathways are possible for a single molecule, with the body continuing to metabolize until the molecule is hydrophilic enough for excretion.
- 📚 Students are expected to understand the general requirements of Phase I and II metabolism, predict metabolic transformations, and identify key intermediates and enzymes involved in these processes.
Q & A
What is the primary purpose of drug metabolism?
-The primary purpose of drug metabolism is to enhance the removal of drug molecules from the body by altering or adding functional groups to make them more water-soluble and easier to excrete.
How does drug metabolism affect the activity of compounds?
-Drug metabolism can either activate or inactivate compounds. It can convert a less active drug into a more active compound or deactivate drugs that are too potent, and it can also detoxify toxic compounds.
What are the two main phases of drug metabolism?
-The two main phases of drug metabolism are Phase I and Phase II. Phase I generally involves oxidation, reduction, and hydrolysis to make the molecule more water soluble. Phase II involves conjugation reactions that add an endogenous molecule to further enhance water solubility.
Which organ is the primary site for drug metabolism?
-The liver is the primary site for drug metabolism, although other organs such as the gastrointestinal tract, kidneys, lungs, and even the skin and placenta can also participate in the process.
What is the role of the Cytochrome P450 enzymes in Phase I metabolism?
-Cytochrome P450 enzymes play a crucial role in Phase I metabolism by oxidizing drugs. They are involved in the addition of oxygen to the drug molecule, which can involve the loss of an electron and an increase in the oxidation state.
How does the presence of certain functional groups on an aromatic ring affect its metabolism?
-The presence of electron-donating substituents on an aromatic ring makes it more likely to undergo hydroxylation, while electron-withdrawing substituents make hydroxylation less likely. Unsubstituted rings or those with electron-donating groups are primarily hydroxylated at the para position.
What is the significance of the reactive intermediate formed during aromatic ring hydroxylation?
-The reactive intermediate formed during aromatic ring hydroxylation is an epoxide, which can react with nucleophilic molecules in the body to generate potentially toxic metabolites. However, if glutathione attacks first, it can bind to the epoxide, detoxify the metabolite, and allow for its excretion.
What are some factors that can affect drug metabolism?
-Factors that can affect drug metabolism include the site of metabolism, age-related considerations, genetic polymorphism, the route of drug administration, and the physical chemical properties of the drug itself.
How does the body ensure a molecule is hydrophilic enough for excretion?
-The body continues to metabolize the xenobiotic through various pathways, including oxidation, reduction, and hydrolysis, until the molecule is deemed hydrophilic enough to be excreted, typically through the kidneys.
What is the role of glutathione in drug metabolism?
-Glutathione acts as a scavenger of toxic xenobiotics. It can react with electrophilic compounds through a process called Michael addition to form glutathione conjugates, which are less toxic and can be excreted from the body.
Can you provide an example of a drug that undergoes both Phase I and Phase II metabolism?
-An example of a drug that undergoes both Phase I and Phase II metabolism is acetaminophen. In Phase I, it can be oxidized to form a reactive intermediate, and in Phase II, it can be conjugated with glutathione to form a non-toxic metabolite that can be excreted.
Outlines
🌟 Introduction to Drug Metabolism
The lecture begins with an introduction to drug metabolism, emphasizing its role in facilitating the removal of drugs from the body. It highlights the importance of drug metabolism in activating prodrugs, inactivating drugs, and detoxifying toxic compounds. The lecture aims to provide an understanding of the general requirements of cytochrome P450 oxidation and the factors influencing enzyme effects. It also covers predicting metabolic transformations for given drugs through phase one and phase two mechanisms, and identifying key intermediates and responsible enzymes.
🔬 Phase One and Two Metabolism
This paragraph delves into the specifics of phase one and phase two metabolism. Phase one focuses on making the drug molecule more water-soluble through oxidation, reduction, and hydrolysis. Phase two involves conjugation reactions that add endogenous molecules to the drug to further enhance its water solubility. Factors affecting metabolism, such as the site of drug metabolism (primarily the liver), are discussed, along with practical considerations like age, genetic polymorphism, and route of administration. The physical chemical properties of the drug and its hydrophilicity or hydrophobicity are also highlighted as influencing factors.
🧬 Cytochrome P450 and Other Enzymes in Metabolism
The paragraph discusses the role of cytochrome P450 enzymes in the oxidation process during phase one metabolism. It explains the naming convention of these enzymes and their specificity for certain positions on the drug molecule. Other enzymes like alcohol dehydrogenase and aldehyde dehydrogenase are also mentioned. The paragraph provides examples of oxidation reactions, including the loss of hydrogen or alkyl groups and the gain of oxygen. It also touches on the steric hindrance and electronic effects of substituents on aromatic rings that can influence the site of oxidation.
⚠️ Potential Dangers of Aromatic Ring Metabolism
This section warns of the potential dangers associated with the metabolism of drugs containing aromatic rings. It explains how the formation of reactive arene oxides can lead to the creation of toxic metabolites. The role of glutathione in detoxifying these metabolites is highlighted. The paragraph also explores the possibility of multiple hydroxylations occurring at different sites on the aromatic ring and the impact of electron-donating and electron-withdrawing substituents on the likelihood of hydroxylation.
🔄 Aliphatic and Aromatic Hydrocarbon Metabolism
The metabolism of aliphatic and aromatic hydrocarbons is explored, with a focus on the oxidation of alkene groups. The necessity for hydrogen presence on the carbons of the alkene for oxidation to occur is emphasized. The paragraph also covers the formation of reactive epoxides and their potential to form adducts with proteins and nucleic acids. Specific examples, such as the metabolism of tamoxifen and the requirements for hydroxylation at benzylic positions, are provided.
🌀 Omega Oxidation and Deamination Reactions
The paragraph discusses omega oxidation, which occurs at the omega or omega minus one position of a hydrocarbon chain. Examples given include losartan and ibuprofen, highlighting the potential for multiple oxidation sites. The concept of oxidative deamination and diamination is introduced, explaining how these reactions lead to the release of amines and the formation of aldehydes or ketones. The role of enzymes in these processes is also mentioned.
🛠️ Enzymatic Functions in Metabolism
This section focuses on the specific enzymatic functions involved in drug metabolism. It covers the conversion of alcohols to aldehydes and carboxylic acids by alcohol dehydrogenase and aldehyde dehydrogenase. The paragraph also discusses benzylic oxidation and the formation of phenols and ketones. The complexity of predicting metabolic pathways due to the various possible reactions is acknowledged.
⚡️ Sulfur and Halogen Group Metabolism
The metabolism of compounds containing sulfur atoms is detailed, including S-alkylation, S-oxidation, and desulfuration. Examples such as captopril and ranitidine illustrate these processes. The paragraph also explains oxidative dehalogenation, which removes halogens from aliphatic chains but not from aromatic rings. The reduction reactions in phase one metabolism, facilitated by enzymes like aldo-keto reductase, are also discussed.
🔄 Reduction Reactions in Metabolism
This section continues the discussion on reduction reactions, particularly focusing on the conversion of nitro groups to amines through nitroso and hydroxylamine intermediates. The reduction of warfarin and methadone to their respective alcohol metabolites is highlighted. The importance of recognizing the major and minor metabolites in the context of exams and practical applications is emphasized.
🧲 Hydrolysis and Conjugation Reactions
The role of hydrolysis in breaking down esters, amides, and lactones is explained, with examples of the enzymes involved, such as esterases and amidases. The paragraph then transitions to phase two metabolism, focusing on conjugation reactions. Glucuronidation, sulfation, amino acid conjugation, acetylation, and methylation are discussed, along with the respective enzymes and cofactors necessary for these reactions.
🌿 Glutathione Conjugation and its Significance
Glutathione is presented as a critical scavenger of toxic xenobiotics in the body, with its conjugation facilitated by glutathione S-transferase. The paragraph outlines the process of glutathione conjugation, the formation of cysteine conjugates, and subsequent reactions like acetylation to form non-toxic metabolites. Examples with acetaminophen and other molecules demonstrate the practical application of glutathione in detoxification.
🔋 Formation of Activated Intermediates in Conjugation
The final paragraph discusses the formation of activated intermediates or cofactors in conjugation reactions, such as acyl coenzyme A and its role in reactions with acetyl transferases. The paragraph also covers the involvement of N-acetyl transferase and other enzymes in the transfer of methyl groups to xenobiotics. The self-explanatory nature of enzyme names in determining their function is highlighted as a useful tool for understanding and predicting metabolic reactions.
Mindmap
Keywords
💡Drug metabolism
💡Cytokine P450
💡Phase one metabolism
💡Phase two metabolism
💡Xenobiotics
💡First-pass metabolism
💡Genetic polymorphism
💡Glucuronidation
💡Sulfation
💡Amino acid conjugation
💡Glutathione conjugation
Highlights
Drug metabolism's primary purpose is to enhance the removal of drug molecules from the body by altering or adding functional groups.
Drug metabolism is crucial for activating prodrugs, inactivating drugs, and detoxifying toxic compounds.
Phase one metabolism aims to increase water solubility through oxidation, reduction, and hydrolysis.
Phase two metabolism involves conjugation reactions that further enhance water solubility for excretion.
The liver is the primary site for drug metabolism, but other organs can also participate.
Factors affecting drug metabolism include age, genetic polymorphism, and the route of drug administration.
Physical chemical properties of a drug influence the extent of metabolism, with hydrophilic drugs undergoing less metabolism compared to hydrophobic ones.
Cytochrome P450 enzymes are key in phase one metabolism, oxidizing specific positions of cholesterol.
Aromatic rings in drugs can undergo oxidation at specific positions, influenced by the presence of electron-donating or withdrawing substituents.
Reactive intermediates like arene oxides formed during metabolism can be toxic and require detoxification.
Multiple hydroxylations can occur at different places on a molecule, leading to various metabolites.
Omega oxidation targets the omega or omega minus one position of aliphatic chains.
Oxidative deamination and diamination are enzyme-catalyzed reactions that modify amines.
Dealkylation reactions result in the removal of alkyl side chains from a molecule.
Hydrolysis of certain functional groups, like esters and amides, is an important phase one metabolic pathway.
Phase two metabolism includes various conjugation reactions that prepare drugs for excretion.
Glucuronidation, sulfation, and amino acid conjugation are key phase two reactions involving endogenous compounds.
Enzymes such as UDP-glucuronosyltransferase, sulfotransferases, and N-acetyltransferase are crucial for phase two metabolism.
Glutathione conjugation plays a vital role in detoxifying toxic xenobiotics and electrophiles.
Methylation reactions, facilitated by methyltransferases, transfer methyl groups to xenobiotics.
Transcripts
Browse More Related Video
Pharmacokinetics and Pharmacodynamics
Six types of enzymes | Chemical Processes | MCAT | Khan Academy
Dosage Calculations Made Easy | Reconstitution Calculation Medication Problems Nursing Students (10)
Medical calculations, part 2, Veterinary Pharmacology
How Drug Trafficking Actually Works — From Heroin to Cocaine | How Crime Works | Insider
Biosynthesis of polyketide natural products
5.0 / 5 (0 votes)
Thanks for rating: