Drug Transporters (Ch 5)

Question 1

what is the role of drug transporters in the cell?

Answer 1

reaching the site of action

permeation

Question 2

characteristics of special carriers

Answer 2

transports endogenous substances (hormones, glucose, AAs)

localized to barrier membranes of the body

expressed on membranes that separate particularly susceptible organs from the rest of the body (brain, placenta, testes)

have a role of drug absorption and can facilitate or prevent drug entry into the body

Question 3

drug efflux transporters

Answer 3

multidrug resistant cancers (MDR)

have efflux pumps – they pump the drug out of the cell
+a cell survival mechanisms

broad substrate specificity

most are ATP-binding cassette transporters (ABC)

Question 4

what is a “NBD”

Answer 4

nucleotide binding domain (ATP binds here and shifts conformation)

Question 5

apical surface vs basal membrane

Answer 5

apical surface AKA the “top” of the cell

basal membrane AKA the “basement”/floor

Question 6

ABCB1

Answer 6

broadest substrate specificity
+antineoplastics (cancer therapies), HIV protease inhibitors, abx, antidepressants, antiepileptics, and opioids

increased expression in certain cancers (screened using pharmacogenetics)

found in GI tract, kidney, liver, testes, and critically important on BBB (primarily apical surface)

Question 7

which drugs inhibit ABCB1

Answer 7

cyclosporine A
quinidine
ritonavir

important because drugs (like digoxin) might be decreased in removal from the body

ex) transplant patient on cyclosporine A also on digoxin for CHF might have decreased removal from the body and will have increased toxicity

Question 8

ABCB1 in the gut

Answer 8

loperamide - an opioid as an antidiarrheal

loperamide does not go anywhere besides the gut; no CNS effects

BUT when taken with quinidine (ABCB1 inhibitor), can achieve systemic absorption and will have CNS effects such as respiratory depression

Question 9

ABCC

Answer 9

largest class (multiple proteins)
mainly antineoplastic drug efflux

Question 10

ABCG2

Answer 10

“breast cancer resistance proteins (BCRP)”

mainly antineoplastics, toxins, food-borne carcinogen efflux

used in folate transport as well (important during pregnancy)

Question 11

intestine efflux transporters

Answer 11

1. transporters localized on apical surface of microvilli
2. intestinal lining has epithelial cells with mostly transporters moving INTO the cells > liver metabolism
3. some transporters transport to blood and some efflux drug BACK into INTESTINE

Question 12

placental efflux transport

Answer 12

1. placenta is very susceptible to xenobiotics

2. drugs normally effluxed back into MOTHER’S bloodstream (protective to fetus)

3. some may cross the placenta into the fetus but will get effluxed right back into placenta

Question 13

BBB efflux transport

Answer 13

1. most drugs do NOT cross into BBB
2. most drugs get effluxed back into blood
3. highly regulated

Question 14

blood-CSF efflux transport

Answer 14

1. most drugs will not cross blood-CSF barrier, although not as highly regulated as BBB
2. less efflux
   3. some drugs administered intrathecal (bupivicaine for epidural)

Question 15

liver efflux transport

Answer 15

1. most drugs will get INFLUXED into the liver (to screen for toxicity and get metabolized)
2. liver is where phase I and II metabolism occurs as well as where all the CYP450 enzymes are
3. some will end up back in the blood, but most drugs end up in the BILE

Question 16

kidney efflux transport

Answer 16

1. most drugs pass through TUBULES and will end up back in the glomerulus
2. some go back into bloodstream, but most go back through glomerulus to get excreted in the URINE

Question 17

BBB structure (4)

Answer 17

composed of:
1. ABC transporters
2. vascular epithelium (blood vessel lining)
3. astrocytes
4. pericytes

the capillaries in the brain do not have gaps; contain very tight junctions to prevent drugs from slipping between cells

glucose and O2 can cross

Question 18

transport systems in BBB

Answer 18

1. transcellular lipophlic pathway > some lipophilic drugs (ethanol, nicotine) will cross the BBB and stay there, but most will actively get effluxed right back out
2. carrier protein-mediated pathway > allows crossing of the BBB for essential brain substrates (glucose, A.A. nucleotides)
3. receptor mediated endocytosis > engulfs substrates (insulin, transferrin, IgG), crosses BBB, and fuses with membrane to drop off into brain
4. adsorptive endocytosis > entire structure endocytoses substrates (albumin, histone) and crosses the BBB in its entirety to deliver to brain
5. simple diffusion > allows O2 and CO2

Question 19

tylenol metabolism in the GI TRACT

Answer 19

normally, tylenol is detoxified by glucuronidation in the LIVER

the ABCC transporters transfer glucuronides from hepatic metabolism back into intestines

1. tylenol undergoes first pass metabolism in the liver; some tylenol will cross the BBB to treat pain (COX2 inhibitor)
2. phase II metabolism (glucuronidation) occurs
3. nontoxic glucuronide goes to bile
4. ABCC recognizes glucuronide and pumps drug into the INTESTINES
5. intestine to feces for elimination