Study guide Chapter 4: Biotransformation

Question 1

What is Hepatic Clearance?

Answer 1

Hapeatic clearance = Hepatic blood flow (Q) x Extraction (E)

CL(H) = Q(H) x E(H); actual clearance relies on extraction ratio and blood flow to the liver.

Question 2

Define drug biotransformation.

Answer 2

Metabolism that transforms drugs into different forms, making them less active or more active (prodrugs).

Primarily occurs in the liver.

Question 3

What is a prodrug?

Answer 3

A drug that becomes more active due to biotransformation.

Example: Codeine is a prodrug that gets converted to morphine.

Question 4

What is an active drug?

Answer 4

Drugs that bind to their binding sites and are excreted without undergoing biotransformation.

Example: Morphine.

Question 5

Examples of Prodrug and Active drug and the phase reactions if any

Answer 5

Prodrug: Codeine–Phase I reaction—morphine, and then morphine can go bind
Active drug: Morphine– can go through phase I or phase II and be activated or inactivated. Main point is morphine doesnt have to get convert

Question 6

What is the first pass effect?

Answer 6

Oral drugs are metabolized by the liver before reaching systemic circulation.

Question 7

Describe the route of blood through the liver.

Answer 7

Blood from the intestines goes to the hepatic portal vein, then to sinusoids, hepatic vein, vena cava, and systemic circulation.

Question 8

What are hepatocytes?

Answer 8

Liver cells that have transporters for drugs and can biotransform them (transform them via phase I and phase II reactions).

Question 9

What is the difference between IV and oral drug administration regarding the first pass effect?

Answer 9

IV does not undergo the first pass effect; the liver does not encounter the drug before systemic circulation.

Question 10

Decribe hepatic blood flow for an oral drug

Answer 10

Absorbed in the GI tract—hepatic portal vein—sinusoids—hepatic vein—vena cava—systemic circulation

Question 11

Describe the hepatic blood flow for an IV drug

Answer 11

Hepatic artery—sinusoids—hepatic vein—vena cava—systemic circulation

Question 12

List the major Phase I metabolic reactions.

Answer 12

• Oxidation
• Reduction

Changes the drug to make it more polar, often resulting in inactivation.

Question 13

What is the role of cytochrome P450 in Phase I metabolism?

Answer 13

Enzyme that transforms drugs from hydrophobic to hydrophilic through reducation and oxidation.

Question 14

What are the most commonly associated P450 isoforms?

Answer 14

• CYP3A4 (responsible for 50% of Phase I metabolism)
• CYP2B6 (8%)
• CYP2D6 (20%)
• CYP1A2

Question 15

What characterizes Phase II metabolic reactions?

Answer 15

Attachment of larger molecules (e.g., carbohydrates, methyl) to increase water solubility.
“slap” something onto the drug

Question 16

What is glucuronidation?

Answer 16

Phase II reaction where glucose is transferred to a molecule, increasing its aqueous solubility, which increases urinary excretion

Question 17

What is Glutathione-S-Transferase (GST)

Answer 17

Enzyme that will transfer glutathione molecule to xenobiotics. glutathione is ubiquitous

Question 18

Define ‘wild type’ CYP enzymes.

Answer 18

the version most often in the population, notated with an asterisk (e.g., CYP1A2*1).

Question 19

What is hepatic enzyme induction?

Answer 19

Increasing the amount of CYP450 enzymes.

Question 20

What is hepatic enzyme inhibition?

Answer 20

Decreasing the amount of CYP450 enzymes.

Question 21

What happens to drug metabolism if a CYP450 enzyme is induced?

Answer 21

Increased activation or inactivation of drugs depending on whether they are prodrugs or active drugs.

Question 22

Describe the metabolism of acetaminophen at normal doses.

Answer 22

Undergoes glucuronidation and sulfation, resulting in non-toxic metabolites excreted via bile.

Question 23

What happens to acetaminophen in overdose situations?

Answer 23

Phase II pathways are overwhelmed, leading to activation of Phase I pathways that produce toxic intermediates. The body has a safety mechanism using GST (phase II) to convert the toxic intermediates and detoxify it.
Once the glutathione is all used up, that can result in liver cell death (toxic metabolites) by destroying liver cells (hepatocytes)

Question 24

What is the role of glutathione in acetaminophen metabolism?

Answer 24

Attaches to toxic intermediates to create non-toxic compounds, but is limited in quantity.

Question 25

List additional factors affecting drug metabolism.

Answer 25

ADDS-EG * Age * Diet * Disease state * Sex * Environment * Genetics

Question 26

What effect does grapefruit juice have on drug metabolism?

Answer 26

Inhibits CYP3A4.

Question 27

What is the effect of charcoal broiling on drug metabolism?

Answer 27

Induces CYP1A2.