PPT 4

Question 1

What is the primary biotransformation organ?

Answer 1

Liver - hepatocytes

Question 2

Describe the first-pass effect of oral medications

Answer 2

Hepatic portal system
GI → local veins (intestinal capillaries) → hepatic portal vein (combines with splenic vein)→ Sinusoids (very leaky capillaries) → Hepatic vein → Vena cava → Systemic Circulation

Question 3

Describe the route an IV medication takes in regards to hepatic blood flow

Answer 3

Systemic Circulation → hepatic artery → Sinusoids → Hepatic vein → Vena cava → Systemic Circulation

Question 4

Hepatic portal vein and hepatic arteries combine to form ________

Answer 4

sinusoids

Question 5

Describe the oxygenation of the blood in the sinusoids

Answer 5

Mixture of deoxygenated blood from heaptic portal vein and oxygenated blood from hepatic artery
Lower oxygen environment, lower than systemic circulation

Question 6

________ are the cells that absorb a drug from leaky sinusoids, where biotransformation takes place

Answer 6

Hepatocytes

Question 7

What are the reactions the liver uses to complete biotransformation?

Answer 7

Phase I and phase II reactions - help with clearance or excretion of drug

Question 8

Differentiate between phase I and phase II reactions

Answer 8

Phase I - make drug more polar
- add or unmask a functional group on an enzyme (small)
Phase II - conjugation reactions, often detoxifying
- adding bigger molecules on drug (glucuronidation)

Question 9

What are the 4 phase I reactions?

Answer 9

Oxidation, reduction, dehydrogenation, and hydrolysis

Question 10

The vast majority of drugs are modified by _______ in phase I reactions

Answer 10

oxidation

Question 11

Describe the steps to cytochrome P450 oxidation

Answer 11

1. Drug binds to CYP
2. CYP is reduced by flavoprotein (P450 reductase)
   - Flavoprotein is reduced by NADPH
3. Oxygen attaches to CYP
4. Oxygen attached to drug, CYP is oxidized
5. Oxidized drug is released (more hydrophobic with -OH instead of -H)

Question 12

30% of drugs undergoing phase I reactions are oxidized by ________

Answer 12

CYP3A4 - substrate specificity low
- 50% of oxidation reactions

Question 13

What are the 3 most important cytochrome P450 types?

Answer 13

CYP3A4, CYP2D6, and CYP2B6
2B6 < 2D6 < 3A4
B less than D, 2’s less than 3

Question 14

Cytochrome 450 enzymes are _________

Answer 14

oxidases

Question 15

Cytochrome p450 oxidation occurs in the ________ of the hepatocyte

Answer 15

Sarcoplasmic endoplasmic reticulum

Question 16

How is the WT indicated?

Answer 16

*1 - most commonly seen in population
- everything else is mutant

Question 17

Polymorphic variants

Answer 17

mutations from the WT that can have greater, less, or the same amount of activity of the WT (*1)

Question 18

Drugs that increase cytochrome P450 activity

Answer 18

induction

Question 19

Drugs that decrease or irreversibly inhibit cytochrome P450 activity

Answer 19

inhibition

Question 20

Cytochrome P450 induction causes a decreased drug effect – IF metabolism ________ drug

Answer 20

deactivates

Question 21

Cytochrome P450 induction causes an increased drug effect – IF metabolism ________ drug

Answer 21

activates

Question 22

Cytochrome P450 inhibition causes an increased drug effect – IF metabolism ________ drug

Answer 22

inactivates

Question 23

Cytochrome P450 inhibition causes a decreased drug effect – IF metabolism ________ drug

Answer 23

activates

Question 24

If a patient who is on warfarin eats a lot of Brussel sprouts, what effect would they have on the medication? (Brussel sprouts are an inducer of CYP1A2 and warfarin is inactivated by CYP1A2)

Answer 24

A lot more inactivation of warfarin - less effect of medication

Question 25

What are the 7 types of conjugation?

Answer 25

glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfation, methylation, and water conjugation

Question 26

What is the most important type of conjugation?

Answer 26

glucuronidation

Question 27

How do uridine diphosphate glucuronyltransferases (UGTs) glucuronidate a drug?

Answer 27

Uridine diphosphate (carrier molecule) adds glucuronic acid to drug

Question 28

Glucuronidation and Glutathione-S-transferase (GST) make a drug more _______ and increase _______

Answer 28

Water soluble, urinary excretion

Question 29

How does Glutathione-S-transferase (GST) work?

Answer 29

Adds glutathione to a xenobiotic (drug) to make it more water-soluble (detoxification)

Question 30

What is a therapeutic dose?

Answer 30

Normal detox pathways functional – no toxic byproducts

Question 31

What is overdose?

Answer 31

Overwhelm normal pathways, alternative pathways activated – toxic by-products

Question 32

How does a Tylenol overdose occur?

Answer 32

- occurs when limited amount of glutathione exhausted - nucleophilic toxic intermediate binds to cell macromolecules (proteins, cell membrane, carbohydrates) and inactivates them. - leads to liver cell death

Question 33

What are the normal pathways for Tylenol metabolism?

Answer 33

Normal pathways: Phase 2 - glucuronidation and sulfation, creating nontoxic byproducts.

Question 34

What occurs when Tylenol is given in toxic doses?

Answer 34

- Phase 1 - CYP2E1 and CYP3A4, creates reactive toxic intermediates - Phase 2: glutathione conjugation- binds to nucleophilic intermediate to neutralize (backup to toxic pathway)

Question 35

What are the 3 examples of personalized medicine?

Answer 35

6-MP - TPMT mutations, warfarin - CYP2C9, herceptin - HER2 overexpression

Question 36

The Goal of Personalized Medicine

Answer 36

- The Right Dose of - The Right Drug for - The Right Indication for - The Right Patient at - The Right Time

Question 37

Alternative forms of a gene which occur at the same locus

Answer 37

Allele All of the variant forms of a gene that are found in a population

Question 38

Genetic testing is _______ for herceptin treatment of breast cancer

Answer 38

required

Question 39

Genetic testing is _______ for warfarin treatment

Answer 39

recommended

Question 40

Describe the variations in drug response based on pharmacogenomics for 6-MP

Answer 40

1. WT - normal metabolism 2. Heterozygous mutant - metabolize drug slower 3. Homozygous mutant - extra slow metabolizer (TPMT deficient); can be fatal

Question 41

Describe the pharmacogenomics for Warfarin - CYP2C9

Answer 41

Racemic mixture - (S) much more potent than (R) - (S) metabolized by CYP2C9 - If mutation in CYP2C9, warfarin won’t work very well - WT, heterozygous mutant, homozygous mutant - mutants have reduced metabolism and higher warfarin concentrations → more likely to bleed out - (R) metabolized by CYP2C19

Question 42

How does herceptin work in treating breast cancer?

Answer 42

Herceptin aka trastuzumab is a monoclonal antibody that binds to and shuts down the HER2 receptor - If patient not HER2+, herceptin won’t do anything