Drug Transport

Question 1

three factors that are important in controlling durg transport across cell membranes

Answer 1

membrane as barriers

specialized transport mechanisms

physico-chemical properties of drugs

Question 2

three important cell types that influence drug transport across cell membranes

Answer 2

epithelial cells

endothelial cells

cells at site of action

Question 3

primary role of epithelial cells

Answer 3

cover body surfaces and GI tract, mainly involved in drug absorption

increases surface areas for absorption through microvilli and brush borders

slit diaphragms in the podocyte foot processes with open fenestrae with diameters of 6nm for filtration

Question 4

primary role of endothelial cells

Answer 4

line vascular system and important for drug distribution

Question 5

types of capillary endothelial cells

Answer 5

non-sinusoidal and non-fenestrated

non-sinusoidal-fenestrated

sinusoidal fenestrated (liver)

sinusoidal non-fenestrated (bone marrow)

Question 6

fenstrated endothelial cells

Answer 6

found in many capillaries, especially those in the liver and in the renal glomerulus

lipid-insoluble drugs are readily transported across the cell membrane via aqueous diffusion

Question 7

major transvascular exchange for lipid-insoluble drugs

Answer 7

cell unctions of moderate pore size (5nm) as in the interendothelial cell clefts lined with macula occludens junctions

main transvascular exchange for the lipid-insoluble drugs

Question 8

aqueous filtration via structural pathway

Answer 8

large aqueous opening across a capillary endothelial cell that permits passage of molecules 45 kDa or more

hepatic sinusoidal capillaries have fenestrae that allow large molecules including albumin and albumin-bound drugs to go through

bulk flow of water across these fenestrae

Question 9

aqueous diffusion via aquaporins

Answer 9

aquaporins - water permeable only

aquaglyceroporins - water and glycerol permeable as well as molecules less than 150 Da

Question 10

aquaglyceroporins

Answer 10

five subtypes

allows water and glycerol in

drugs that are highly water soluble and have low membrane partition coeffiicents can also take these routes

Question 11

AQP9

Answer 11

an aquaglyceroporin that allows ater, glycerol, urea, carbamides, purines, pyrimidines, and metallic ions to pass through

Question 12

Leishmaniasis

Answer 12

parasitic protozoa of genus leishmania

becomes drug resistant after mutation in aquaglyceroporin channels

button-like scar after recovery

Question 13

types of active transport

Answer 13

primary, secondary, and facilitated diffusion

Question 14

ABC transporters

Answer 14

more than 49 known genes that can group into 7 families (ABCA to ABCG)

ATP-binding cassette transporters couple energy drived from ATP hydrolysis to the translocation of solute across biological membranes against the concentration gradient

system is saturable

system is selective for analogs of naturally occuring water-soluble compounds

mediate only unidirectional efflux

Question 15

P-pg (also known as MDR1 or ABCB1)

Answer 15

an ABC transporter that mediates drug efflux and plays an an important role in drug absorption, distribution, and excretion

blocks entrance of xenobiotics to the brain

reduces absorption at GI

promotes excretion via bile and urine

overexpression in cancer cells can lead to drug resistance

Question 16

SLC transporter

Answer 16

solute carrier allowing solute to go uphill against their electrochemical gradients by coupling to transporting a second solute that flows down its graient

does not require ATP

secondary active transport

Question 17

OATPs

Answer 17

SLC21/SLC0 - organic anion transporter

Question 18

OAT

Answer 18

SLC22 - the organic cation/anion/zwitterion transporter

Question 19

SLC6s

Answer 19

also plays an important role in terminating the transmitter action in the CNS by uptake of transmitters into the terminal and glial cells

Question 20

SLC6A4

Answer 20

serotonin transporter - a target for a major class of antidepressant drugs

called selective serotonin reuptake inhibitors

ex. Prozac, Praxil, and Zoloft

Question 21

facilitated diffusion

Answer 21

a form of SLCs that allow solutes to flow downhill with their electrochemical graidents

Question 22

GLUT2

Answer 22

SLC2A2 - important in transferring glucose intoo skeletal muscles (via facilitated diffusion), which is increased in response to insulin

Question 23

transcellular transport

Answer 23

drugs or solutes are transferred from one side of the cell membrane to the other side of polarized cells such as endothelial and epithelial cells

fenestrated capillaries provide pathways for transcellular transport of larger solutes

Question 24

transcytosis

Answer 24

a vesicle formed on one side of the membrane and the subsequent movement of the vesicle to the other membrane in a polar cell

drugs bigger than 100k Da will be handled this way

Question 25

absorptive-mediated endocytosis

Answer 25

polycationic peptides bind to the negative charges on cell membranes to initiate endocytosis

Question 26

receptor-mediated transport

Answer 26

receptors such as insulin attaches to a receptor and initiates transcytosis

attach molecules to the ligand to allow it to be transported in - Trojan horse method

Question 27

paracellular transport

Answer 27

happens via pathways between cell-cell junctions

lipid-insoluble molecules can take this pathway to cross form one side of the cell to the other side

structural dependence

Question 28

inter-endothelial cell junctions

Answer 28

depending on the location, endothelial cells form different junctions form a very tight junction to macula occludens, or loose junctions

Question 29

permeability of macula occludens

Answer 29

macromolecules as large as myoglobins and horseradish peroxidase

Question 30

vectorial transport

Answer 30

a net transfer of a solute across epithelial or endothelial cells, which is important in the efficient transfer of nutrients across epithelial or endothelial barriers, drug absorption, and excretion

lipid-soluble drugs achieve this because the blood flow maintains a concentration gradient

substrates of ABC transporters achieve this because they are transported out of the gut cell into the blood

Question 31

Loratadine (Claritin) vs. Diphenhydramine (benadryl)

Answer 31

claritin does not cause drowsiness because it is a substrate of MDR1, so it is pumped out of the brain, whereas benadryl is not and remains in the brain and decreases activity

Question 32

Henderson-Hasselbalch equation

Answer 32

log([protonated form]/[unprotonated form]) = pKa - pH

Question 33

chemical and physical properties of drugs in relation to transport

Answer 33

structural similarity to a natural compound

lipid vs. water solubility

Question 34

pKa and absportion

Answer 34

at a fixed pH, absorption of acidic drugs increases with increasing pKA values

absorption of bases increases with decreasing pKa values

Question 35

ion trapping effect

Answer 35

pH across the cell membrane determines the distribution of drugs between two sides of the membrane

for an acidic drug, the more alkaline the phase is, the more drugs will be accumulated

Question 36

ibuprofen and ion trapping

Answer 36

pKa of 4.4, so in the stomach there is 1000 times more unprotonated acid inside the cell, trapping them there

in the intestines, there is ten times more, but that is enough given the duration of time the drug is in the intestines and also the absorptive surface area in the intestines

Question 37

ion trapping and excretion

Answer 37

accelerated excretion can be achieved if the drug is in the ionized form when in the urine