Pharmacokinetics | Drug Metabolism

Name: Pharmacokinetics | Drug Metabolism
Uploaded: 2022-08-05T14:00:25.000Z
Duration: 56 min 6 s

Drug Metabolism

In this section, the speaker discusses drug metabolism and how drugs are excreted from the body. The liver plays a crucial role in metabolizing drugs, converting them into inactive forms that can be easily excreted.

Drug Metabolism Pathways

There are three different ways that drugs can be metabolized:

Converting toxic substances into non-toxic ones

Activating pro-drugs

Inactivating active drugs to make them easier to excrete.

The liver has special enzymes that work on these drugs, breaking them down through two phases of biotransformation: phase one and phase two.

Not all drugs go through both phases; some may only undergo one or bypass phase one altogether.

Enzymes Involved in Drug Metabolism

The smooth endoplasmic reticulum and mitochondria in hepatocytes contain special enzymes involved in drug metabolism.

These enzymes include cytochrome P450 systems, which play a crucial role in activating pro-drugs like valacyclovir.

Importance of Inactivating Drugs

Inactivating active drugs is important because it makes them easier to excrete from the body.

Once a drug has exerted its effect, it's time for it to be excreted so that it doesn't build up in the body and cause harm.

Liver Anatomy

This section focuses on the anatomy of the liver and its cells, specifically hepatocytes. The smooth endoplasmic reticulum and mitochondria within hepatocytes contain special enzymes involved in drug metabolism.

Hepatocyte Structure

Hepatocytes are liver cells responsible for many functions including drug metabolism.

They contain smooth endoplasmic reticulum and mitochondria where drug metabolism occurs.

The smooth endoplasmic reticulum is responsible for phase one biotransformation, while the mitochondria are involved in phase two.

Importance of Drug Metabolism

Drug metabolism is important because it helps to convert drugs into inactive forms that can be easily excreted from the body.

Without drug metabolism, drugs would build up in the body and cause harm.

CYP 450 Enzymes

In this section, the speaker discusses the different types of families of CYP 450 enzymes and their importance in metabolizing drugs.

Types of CYP 450 Enzymes

The CYP 450 system has two important types of enzymes: CYP3A4 and CYP2D6.

The cytochrome family consists of heme-containing enzymes.

The first number in the enzyme name refers to the family, while the second letter refers to the subfamily and the third number isozyme.

Functions of CYP 450 Enzymes

The two most important enzymes are responsible for metabolizing almost all drugs: CYP3A4 (70-75%) and CYP2D6 (20-25%).

These enzymes convert active drugs into inactive ones or toxic metabolites into non-toxic ones through oxidation, reduction, or hydrolysis reactions.

This conversion makes drugs more polar and water-soluble so that they can be easily excreted from the body.

Factors Affecting Enzyme Function

Polymorphism can affect how readily an enzyme can metabolize a drug, making it either super quick or super slow.

Rapid metabolizers are common with polymorphisms in the cyp2d6 enzyme.

Phase 1 Metabolism

In this section, the speaker discusses the importance of phase 1 metabolism and how it affects drug concentration in the body.

Rapid Metabolizers

Patients who are rapid metabolizers will decrease the concentration of active drugs, leading to decreased therapeutic effects.

CYP2D6 is an example of a system that can act as a rapid metabolizer.

Rapid metabolizers form more inactive drug that is easily excreted, decreasing the therapeutic effect of the drug.

Slow Metabolizers

Patients who are slow metabolizers will have high concentrations of active drugs, leading to toxic side effects.

CYP450 system polymorphism can cause patients to act as slow metabolizers.

Slow metabolizers take longer to convert active drugs into inactive ones, resulting in less inactive drug being formed and more active drug remaining in the blood.

Polypharmacy

Many people take multiple medications at once, which can interact with each other via liver metabolism.

Other drugs taken by a patient could be interacting with the CYP450 system and altering the metabolism of other drugs they may be taking.

Example: Warfarin

Warfarin is an anticoagulant that thins out blood and decreases clotting.

If a patient takes another drug that acts as a CYP450 inducer, it will increase activity in this enzyme and decrease warfarin's effectiveness.

This results in increased inactive drug and decreased active drug concentrations, increasing risk for clotting.

Factors Affecting Phase One Metabolism

In this section, the speaker discusses factors that affect phase one metabolism, which is primarily carried out by the CYP450 system. The speaker explains how certain drugs can act as inhibitors or inducers of the CYP450 system and how this can lead to toxic side effects or sub-therapeutic effects.

Drugs That Can Alter CYP450 Enzymes

Certain drugs can alter CYP450 enzymes, acting as inhibitors or inducers.

There are many drugs that can potentially interact with specific types of CYP450 enzymes, and some may only act as inducers or inhibitors of a specific type of enzyme.

If a drug acts as a CYP450 inducer, it increases the activity of the enzyme and decreases the concentration of therapeutic drug being metabolized. Conversely, if a drug acts as an inhibitor, it decreases the activity of the enzyme and increases the concentration of therapeutic drug being metabolized.

Liver Disease and Age

The liver is the primary spot for metabolism; therefore, patients with liver disease will have decreased efficacy in their CYP450 system.

Elderly individuals and infants also have decreased efficacy in their CYP450 system due to age-related changes.

Factors Affecting Phase Two Metabolism

In this section, the speaker discusses phase two biotransformation.

Phase Two Biotransformation

Phase two biotransformation involves conjugation reactions that add a polar molecule to the drug, making it more water-soluble and easier to excrete.

The most common conjugation reactions involve glucuronidation, sulfation, and acetylation.

Conclusion

Understanding the factors affecting phase one and phase two metabolism is important for predicting drug interactions and potential toxic side effects.

Phase One and Two Biotransformation

In this section, the speaker explains that phase two biotransformation can occur before or after phase one. The purpose of phase two is to make drugs more polar and water-soluble so they can be easily excreted. This is achieved by using transferase enzymes to add on methyl, acetyl, sulfur, glutathione, or glucuronate groups.

Phase Two Biotransformation

Phase two occurs after phase one and makes drugs more polar and water-soluble for easier excretion.

Transferase enzymes are used in phase two to add on different groups such as methyl, acetyl, sulfur, glutathione, or glucuronate.

Adding these groups increases the polarity of the drug making it easier to excrete into the biliary system or urine.

The process of adding these groups onto a slightly polar molecule is called conjugation reactions.

Significance of Phase Two Biotransformation

Cytochrome P450 system is used in phase one to convert active drugs into inactive ones.

After going through both phases, drugs become more polar and water-soluble which makes them easier to excrete.

Understanding the process of adding different groups onto a slightly polar molecule helps understand how easy it will be to excrete the drug.

Pharmacokinetics: Drug Metabolism and Excretion

In this video, the speaker discusses drug metabolism and excretion in pharmacokinetics. The video covers conjugation reactions, phase one and two reactions, and the impact of inhibitors on drug metabolism.

Conjugation Reactions

Drugs can go through phase one or both phase one and two reactions.

Phase one reactions include oxidation, reduction, and hydrolysis.

Phase two reactions include acetylation, methylation, glucuronate additions, glutathione addition, sulfation.

Phase two enzymes add a group to the drug to make it more water-soluble for easier excretion.

Impact of Inhibitors on Drug Metabolism

CYP450 inhibitors like ketoconazole, erythromycin, ritonavir, ameprazole inhibit the enzyme system that converts pro-drug into active drug.

Clopidogrel is a pro-drug that gets converted from inactive form to active form by CYP450 system.

Ameprazole inhibits CYP450 system which reduces clopidogrel activity leading to reduced antiplatelet activity.

Reduced antiplatelet activity increases the risk of myocardial infarction (MI).

Practice Problems

Question 6: Which reaction represents a phase two reaction?

Amination is not involved in phase two reactions.

Sulfation is involved in phase two reactions as transferase enzymes add sulfur group to drugs making them more polar for easier excretion.

Excretion

The next chapter of pharmacokinetics after metabolism is excretion of drugs.