Chapter 5: Pharmacogenomics and Drug Transporters

Question 1

Define pharmacogenomics and its importance in personalized medicine

Answer 1

The study of how an individual’s genetic makeup affects their response to drugs.

It is important for personalized medicine because it allows for predicting drug efficacy and toxicity based on a patient’s genetic profile.

Question 2

What does idiosyncratic mean?

Answer 2

Unusual drug response

Question 3

Name and describe three drugs that may require dosage adjustments in specific genetic populations, the enzyme or mutation responsible, and the type of testing done to determine susceptible populations.

Answer 3

1. Herceptin which blocks the Her2 receptor on cancer cells
   -Her2
   -Required Biopsy to see if cancer is HER2-positive (over expressing Her2)
2. Warfarin which is metabolized by CYP2C9
   -CYP2C9
   -Recommended genetic testing for dose adjustments based on CYP2C9 genetic variants
3. Codeine - Dosage adjustments based on CYP2D6 genetic variants, which affect conversion of codeine to the active metabolite morphine.
   required prior to 6MP administration

Question 4

How many gene bases do we have?

Answer 4

3.2 billion base PAIRS

6.4 billion bases with both strands

Question 5

_____% of DNA codes for protein

Answer 5

1-2%

Question 6

_____ % of us have the same DNA

Answer 6

99.9

Question 7

How many genes do we have?

Answer 7

30,000

Question 8

How many Single base pairs variants (Single nucleotide polymorphism or SNP) do we have?

Answer 8

More than 1 million

Question 9

What is an locus/loci?

Answer 9

Exact location on a chromosome

Question 10

What are alleles?

Answer 10

An alternate form of a gene at the same loci

Question 11

What is a silent mutation?

Answer 11

The different allele doesnt change the amino acid and is not even detectable unless theres a DNA scan.

Question 12

What does PM stand for?

Answer 12

Poor Metabolizer

Question 13

Prodrug + poor metabolizer =

Answer 13

Drug cannot be activated that well. Wont reach its full efficacy
Accumulation of prodrug because not being metabolized (Not being activated nor excreted)

Question 14

Active drug + poor metabolizer =

Answer 14

High efficacy
Stays in the system longer
Not being metabolized fast therefore not being inactivated fast and not excreting fast (stays in system longer)
May need lower dose and/or longer intervals so wont have toxic levels

Question 15

Prodrug + ultarapid metabolizer =

Answer 15

Works fast, high efficacy

Question 16

Active drug + ultrarapid. metabolizer =

Answer 16

Inactivated quick
Cant even reach its full efficacy because its metabolized and inactivated/excreted so quick

Needs greater dose or slow release

Question 17

CYP2D6

Answer 17

Absent in 7% of Caucasians

Hyperactive in 30% of East Africans

Catalyzes metabolism: Betablockers, Class 1C antiarrhythimcs, Analgesics, Various antidepressants/physchotics

5HT3 inhibitor

Question 18

What activates Codeine?

Answer 18

CYP2D6

Question 19

What inactivates Codeine

Answer 19

CYP3A4 to Norcodeine

Question 20

What is warfarin metabolized by?

Answer 20

CYP2C9

Question 21

Describe Warfarin

Answer 21

Metabolized by CYP2C9
Racemic mixture of R- and S- Warfarin
S- warfarin 7-10x more potent

Question 22

What happens if you carry a variant allele of CYP2C9 while taking warfarin?

Answer 22

Reduced metabolism of warfarin leading to higher concentrations of warfarin therefore higher risk of bleeding.

Question 23

What causes breast cancer?

Answer 23

Overproducing Estrogen and Progesterone receptors

Question 24

What type of treatment is included in breast cancer?

Answer 24

Estrogen deprivation

Question 25

HER2+ cancers respond to what drug?

Answer 25

Herceptin

Question 26

What is required before starting Herceptin?

Answer 26

Biopsy with genetic testing to determine is the tumor is overproducing th HER2 gene

Question 27

Describe the role of drug transporters in the cell

Answer 27

Primary function is to transport endogenous substances Drug transporters play a role in moving or preventing drugs and other substances across cell membranes, facilitating both influx and efflux.

Question 28

Active Transport Requires____

Answer 28

ATP

Question 29

Facilitated diffusion requires a ______

Answer 29

Concentration Gradient

Question 30

What are the special carriers?

Answer 30

Active transport and facilitated diffusion

Question 31

What are 4 specialized barriers?

Answer 31

Blood-brain Blood-placenta Blood-testes Blood-ovarian

Question 32

What does xenobiotic mean?

Answer 32

Something thats been introduced into the body

Question 33

Define the role of drug efflux transporters

Answer 33

Drug efflux transporters, such as the ATP-binding cassette (ABC) transporters, actively pump drugs out of cells, reducing intracellular drug concentrations. This can cause drug resistance.

Question 34

70% of genes are _______

Answer 34

Transporters

Question 35

What are 3 types of passive transporters?

Answer 35

Coupled Exchanger Passive

Question 36

What is a coupled transporter?

Answer 36

It takes 2 things simultaneously through a "sim porter" or coupled transporter Ex) SGLT

Question 37

Passive transport _____ require ATP

Answer 37

does not

Question 38

What is an Exchanger transporter?

Answer 38

1 thing goes out and another goes in. Important in the heart. Ex) NCX

Question 39

What is the most important active transporter?

Answer 39

Na/K ATPase

Question 40

List the most important ABC transporters and differences in their drug affinity

Answer 40

***ABCB1 (broadest substrate specificity including antineoplastics, HIV protease inhibitors antibiotics, antidepressants, antiepileptics, and opioids). They also have a wide distribution in the body (GI, kidney, liver, testes) and are critical to the maintenance of the blood-brain barrier (BBB) - Remember quinidine, cyclosporine A, and Ritonavir are competitive inhibitors to ABCB1 - Digoxin is transported by ABCB1 and, if inhibited, ABCB1 won’t remove as much resulting in toxic plasma levels. - Loperamide typically has no CNS effects but if ABCB1 is inhibited, systemic absorption can occur resulting in CNS effects like respiratory suppression*** - ABCC - Largest class; ubiquitous; antineoplastics drug - ABCG2 is known as the breast cancer resistance protein (BCRP) (antineoplastics, toxins, food-born carcinogens) - Also, an efflux transporter of folate

Question 41

ABC transporter require_____

Answer 41

ATP **ATP binding cassette transporters**

Question 42

Describe an ABC transporter?

Answer 42

Transmembrane spanning domains and NBD (Nucleotide binding domains) intracellularlly. The ATP binds at The C-terminus NBD and then the drug can be pumped out or in to the cell (this depends on the location and orientation of the receptor)

Question 43

What separates the gut from the blood?

Answer 43

The basal membrane (closest to blood) and the apical surface (closest to gut)

Question 44

Analyze the anatomic differences between drug transporters in different organs and their overall effects

Answer 44

Drug transporters are differentially expressed in organs like the intestine, liver, kidney, and blood-brain barrier. This affects drug absorption, distribution, metabolism, and elimination

Question 45

List the components of the intact blood-brain barrier

Answer 45

-The intact blood-brain barrier consists of the vascular endothelium with tight junctions, astrocytes, and podocytes; which together restrict the entry of most drugs into the brain. It has many efflux transporters so even when a drug is allowed in, it may be immediately pumped back out before its effects are seen -Tight junctions and adherens junction complexes

Question 46

Where does the ABCB1 mostly sit?

Answer 46

On the Apical surface

Question 47

Why cant some drugs be taken orally?

Answer 47

Some drugs if taken orally will just get pumped back out by an efflux transporter

Question 48

Where are drugs entered and filtered into the kidney?

Answer 48

The Glomerulus

Question 49

Where are most of the transporters on the BBB?

Answer 49

The vascular epithelium

Question 50

Delineate the pathway of Tylenol in the gut before and after biotransformation

Question 51

Describe the transporters for the Blood-CSF barrier

Answer 51

On the Pia matter and ependymal cells Less efflux Not effective for antineoplastics