Exam 1 - Ch. 5 review

Question 1

Define pharmacogenomics and its importance in personalized medicine.

Answer 1

Helps predict, explain and treat patients specific to their genetic profile. It allows us to tailor doses and treatment plans based on genetic variants for better outcomes.

Question 2

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 2

Herceptin, warfarin, 6-mercaptopurine

all would need genetic testing.

6-mercaptopurine has genetic variation in a gene called TPMT. Some need less of the drug, and some need even less or else it could be fatal.

Herceptin requires a simple blood test

Warfarin is metabolized by CYP2C9, and those with CYP2C9*2 or *3 have reduced metabolism. leads to toxic amounts.

Question 3

Describe the role of drug transporters in the cell membrane

Answer 3

primary: Transport endogenous substances across membrane, mostly passive transport.

Can have a role in drug absorption and can facilitate or prevent drug entry into the body.

Question 4

What % of genes are transporters

Answer 4

7%

Question 5

Majority of transporters have a high:

Answer 5

substrate specificity, such as Na, glucose, amino acids.

Question 6

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

Answer 6

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 (antineoplastics)
ABCG2 is known as the breast cancer resistance protein (BCRP) (antineoplastics, toxins, food-born carcinogens)
Also, an efflux transporter of folate

Question 7

Define the role of drug efflux transporters

Answer 7

Discovered by oncologists because cancer cells were pumping drugs out of their cells. Bind to drugs and transports them into or out of the cell. They increase in numbers when they see more drugs, it’s a cell survival mechanism.

Question 8

Do efflux transporters require ATP?

Answer 8

yes

Question 9

What does ABC transporters stand for?

Answer 9

ATP-binding Cassette Transporters

Question 10

How do ABCs sit on membrane?

Answer 10

Transmembrane spanding domains, NBD on inside.

Question 11

where does ATP bind on a ABC?

Answer 11

To the NBD

Question 12

ABCA1

Answer 12

Cholesterol, can pump in or out

Question 13

ABCB1

Answer 13

Broadest substrate specificity: antineoplastcis, HIV protease inhbitors, antibx, antidepressants, antiepileptics, opioids.

Some cancers increases ABCB1

GI, liver, kidney, testes.

CRITICAL FOR BLOOD BRAIN BARRIER

Question 14

what does ABCB1 do in BBB

Answer 14

Orientated in apical surface to pump drugs out that somehow got into lining

Question 15

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

Answer 15

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 16

List the components of the intact blood-brain barrier

Answer 16

1. ABC transporters
2. Vascular epithelium (tight!!!)
3. Other cells such as astrocyte and podocytes.

Question 17

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

Answer 17

Acetaminophen (Tylenol) is absorbed in the gut and undergoes first-pass metabolism in the liver, where some is conjugated with glucuronic acid (glucuronidation). The glucuronide conjugate is then transported back into the intestine via bile and, instead of being reabsorbed into the bloodstream by ABCG2 transporters, ABCC transporters recognize it as a waste product and pump it back into the intestines to be eliminated in the feces.

Question 18

Blood volumes in body: whole blood and plasma

Answer 18

Whole blood: 5.6L/70kg
Plasma: 2.8L/70kg

Question 19

Characteristics of ABCs (what he drew)

Answer 19

You’ve got the gut, transporters on Apical side of epithelial cells here facing gut, then other side of epithelial cells you got the basal membrane side, which has transporters that allow it into blood stream.

Question 20

Drug interactions for ABCB1

Answer 20

Cyclosporine, quinidine, ritonavir all inhibits ABCB1

e.g. digoxin interacts with one of these above drugs and increases toxicity

Question 21

ABCC

Answer 21

Largest class, ubiquitous, but not as many drugs as ABCB. Antineoplastic

Question 22

ABCG2

Answer 22

Breast cancer resistant protein (BRCP)

Antineoplastics, toxins, food-borne carcinogens, found in GI-tract.

Question 23

Non-ABC drug efflux transporters

Answer 23

no ABC, largely passive.

Question 24

SLC21

Answer 24

type of non-abc

-OATPs
-Some for influx and some efflux, depending on orientation in membrane

Question 25

Most drugs in relation to BBB do not

Answer 25

cross

Question 26

Majority of arrows are pointing in or out of liver?

Answer 26

Into.

Question 27

Majority of arrows are pointing in or out of kidney tubule?

Answer 27

Into

Question 28

8 things that can cross BBB

Answer 28

small lipophilic molecules, O2, CO2, ethanol, nicotine, insulin, glucose, albumin

Question 29

Tylenol animation

Answer 29

Tylenol goes into gut, across bloodstream, to first-pass effect (glucuronidation resulting in glucuronide), put into bile, bile dumps into intestine, the ABC transporters in gi tract recognize the glucuronidation and pump it right back out into intestines to be excreted.