Drug Metabolism Made Simple *ANIMATED*

Summary

This video explains drug metabolism, focusing on how the body processes drugs to make them easier to eliminate. It highlights two types of metabolites: inactive, which lose the drug's original activity, and active, which can retain or even increase the drug's effects. The video describes the difference between Phase 1 (functionalization) and Phase 2 (conjugation) metabolic reactions, using enzymes like cytochrome P450, alcohol dehydrogenase, and glucuronyltransferase. It also discusses bioactivation, toxic metabolites like acetaminophen’s, and prodrugs like enalapril. The liver plays a key role in metabolizing drugs.

Takeaways

• 🧬 Metabolism is the biochemical process that modifies xenobiotics, primarily drugs, to facilitate their elimination.
• 💊 Drug metabolism often starts with a hydrophobic drug, converting it into a hydrophilic metabolite for easier elimination.
• 🔄 The outcome of drug metabolism can result in an active or inactive metabolite, which affects the drug's pharmacological activity.
• 🧪 Inactive metabolites have no effect, such as the breakdown of procaine, while active metabolites, like morphine from codeine, retain or enhance activity.
• ⚙️ Bioactivation occurs when an inactive parent drug (prodrug) is metabolized into an active form, like enalapril converting to enalaprilat.
• ⚠️ Toxic metabolites can be produced during metabolism, such as acetaminophen's metabolite NAPQI, which is harmful to the liver.
• 🧠 Phase 1 metabolism involves functionalization reactions, typically oxidation, reduction, or hydrolysis, increasing drug polarity for easier excretion.
• 🧬 Cytochrome P450 enzymes play a major role in oxidation reactions during drug metabolism.
• ⚗️ Phase 2 metabolism involves conjugation reactions where enzymes transfer polar molecules (e.g., glucuronic acid) to the drug, enhancing excretion.
• 🌱 Glutathione conjugation detoxifies harmful electrophilic compounds, aiding in the excretion of toxic metabolites.

Q & A

What is the primary function of metabolism in the body?

Metabolism is a biochemical process that alters xenobiotics, like drugs, to make them more hydrophilic, facilitating their elimination from the body.

What are the two possible outcomes of drug metabolism?

Drug metabolism can result in either an active metabolite, which retains or enhances the drug's pharmacological activity, or an inactive metabolite, which has no pharmacological activity.

Can you give an example of a drug that produces an active metabolite?

Codeine is an example of a drug that is metabolized into an active metabolite, morphine, through a process called demethylation.

What is a prodrug, and can you give an example?

A prodrug is an inactive parent drug that is metabolized into an active form. An example is enalapril, which is hydrolyzed to enalaprilat, a potent antihypertensive agent.

What can happen during bioactivation, and why is it important?

Bioactivation can sometimes lead to the formation of a toxic metabolite. For example, acetaminophen’s metabolite N-acetyl-p-benzoquinone imine is hepatotoxic, which is why understanding bioactivation is critical for drug safety.

What are Phase 1 metabolic reactions, and what is their purpose?

Phase 1 metabolic reactions involve the functionalization of a drug by oxidation, reduction, or hydrolysis to reveal or add a functional group, increasing the drug's polarity and making it easier to excrete.

What is the role of cytochrome P450 in drug metabolism?

Cytochrome P450 is a superfamily of oxidizing enzymes that play a major role in the oxidation of drugs, which is the most common type of Phase 1 reaction.

How does alcohol dehydrogenase contribute to drug metabolism?

Alcohol dehydrogenase oxidizes alcohols into aldehydes, which can then be further oxidized to carboxylic acids, such as in the conversion of acetaldehyde to acetic acid during ethanol metabolism.

What are Phase 2 metabolic reactions, and why are they important?

Phase 2 reactions are conjugation reactions where a functional group is added to a drug to increase its polarity. This helps in detoxifying the drug and making it easier to eliminate from the body.

Can you explain the process of glucuronidation in Phase 2 metabolism?

Glucuronidation is a Phase 2 reaction where the enzyme glucuronosyltransferase transfers glucuronic acid to functional groups like hydroxyl or carboxyl groups, significantly increasing the drug's hydrophilicity for easier excretion.