PPT 5

Question 1

What are the 4 parameters affecting passive diffusion?

Answer 1

Molecular weight
pKa
Lipid solubility
Plasma protein binding

Question 2

_____ of genes in genome encode for transporter proteins

Answer 2

7%

Question 3

SLC transporters cross barriers via ______

Answer 3

Primarily passive transport (gradients)
Some active - exchanger and coupled transport

Question 4

What do SLC proteins transport?

Answer 4

High substrate specificity - nutrients, ions, metabolites, and drugs

Question 5

What are the 4 types of permeation?

Answer 5

• Aqueous diffusion
• Lipid diffusion
• Endocytosis and exocytosis
• Special carriers

Question 6

What are special carriers? How do they work?

Answer 6

Membrane drug transporters; molecules bind to drugs and move across barriers
Primary function - transport endogenous substances

Question 7

What is the main drug efflux transporter?

Answer 7

ATP-binding cassette (ABC) transporters

Question 8

ABC transporters have ______ substrate specificity

Answer 8

broad

Question 9

What do drug efflux pumps do?

Answer 9

• Pump drug out of cell
• Cell survival mechanism

Question 10

What are nucleotide-binding domains?

Answer 10

ATP binds to NBD

Question 11

What do ABC transporters have in common?

Answer 11

1. Transmembrane spanning domains
2. Nucleotide-binding domain (NBD)

Question 12

ABC transporters are _____ specific

Answer 12

location - apical (top) vs basal (bottom)

Question 13

What are the major drug efflux transporters?

Answer 13

ABC transporters - B, C, G

Question 14

Which ABC transporter has the broadest substrate specificity?

Answer 14

ABCB1

Question 15

_______ is critical in the maintenance of BBB

Answer 15

ABCB1

Question 16

What are the drug interactions with ABCB1?

Answer 16

Drugs that inhibit ABCB1 - Cyclosporine A, Quinidine, Ritonavir

Question 17

Digoxin is transported by ______

Answer 17

ABCB1

Question 18

What will happen if a patient is taking digoxin AND a drug that inhibits ABCB1?

Answer 18

Decreased intestinal removal and increased plasma levels (toxicity) of digoxin - arrhythmias

Question 19

Loperamide is transported by ______

Answer 19

ABCB1

Question 20

How does loperamide work as an antidiarrheal?

Answer 20

Although loperamide is an opioid, since it is transferred by ABCB1 in the gut, it stays in the gut – antidiarrheal
- No CNS effects: GI ABCB1

Question 21

How do people abuse loperamide?

Answer 21

• When given with quinidine (ABCB1 inhibitor)
  - Systemic absorption
  - CNS effects (respiratory suppression)

Question 22

ABCC primarily transports _______

Answer 22

antineoplastic drugs

Question 23

ABCG transports ______

Answer 23

• Breast cancer resistance protein (BCRP)
• Antineoplastics, toxins, food-borne carcinogens
• Folate transport

Question 24

The majority of drugs are absorbed through these barriers in ABC transporters

Answer 24

Intestines, liver, kidneys

Question 25

The majority of the drugs are pumped back out of these barriers via ABC transporters

Answer 25

Placenta, BBB, blood-CSF barrier

Question 26

_______, _______, and _______ prevent drugs from crossing the BBB

Answer 26

ABC transporters The vascular epithelium Other cells - astrocytes and podocytes - regulate how much drug reaches neurons

Question 27

ABC transporters in the GI tract are primarily on the ______ surface

Answer 27

apical - microvilli (increase surface area)

Question 28

Most of the ABC transporters are in the _____

Answer 28

gut and liver Gut - most common – ABCG2 (BCRP), but has all types

Question 29

________ transport out glucuronides from hepatic metabolism back into the intestine

Answer 29

ABCC (MRPs)

Question 30

The liver facilitates xenobiotic metabolism, excretion into____

Answer 30

bile

Question 31

Types of transporters in the liver

Answer 31

SLC type (OATPs), ABCs (all)

Question 32

Lipophilic drugs can cross ____

Answer 32

barriers - BBB, placenta nicotine, alcohol

Question 33

Transporter protein expression is upregulated by:

Answer 33

PXR, steroids, xenobiotics

Question 34

Transporter protein expression is downregulated by:

Answer 34

- Endothelin - Partial agonist - antagonist function

Question 35

xenobiotics

Answer 35

chemical substances that are foreign to the biological system (made outside the body)

Question 36

Regulation of cholesterol in the cell is accomplished by ______

Answer 36

ABCA1 transporter

Question 37

Blood CSF barrier is not as ______ as the BBB

Answer 37

selective

Question 38

How is Tylenol metabolized when taken orally?

Answer 38

From intestine taken into the bloodstream where it undergoes first-pass effect in the liver. Tylenol metabolism is a phase II reaction of glucuronidation (a glucose molecule is attached to the Tylenol) it is now a non-toxic glucuronide. This is put into the bile that then returns to the intestine. It is now recognized by the ABC transporters because of the glucuronidation, it is transported to the intestine where it can be excreted via defecation.

Question 39

Drug transporter direction "flux" is determined by

Answer 39

Their location and what the function of the organ they are located on is

Question 40

The BBB is composed of _____

Answer 40

tight junctions

Question 41

Molecules that can cross the BBB include

Answer 41

Small, lipophilic molecules (O2, CO2, ehtanol, nicotine) - transcellular lipophilic pathway Medium molecules (glucose, amino acids, nucleotides) - carrier protein-mediated pathway Large molecules (insulin, IgG, albumin, histone) - endocytosis