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Flashcards in Drug Transport Deck (37)
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1
Q

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

A

membrane as barriers

specialized transport mechanisms

physico-chemical properties of drugs

2
Q

three important cell types that influence drug transport across cell membranes

A

epithelial cells

endothelial cells

cells at site of action

3
Q

primary role of epithelial cells

A

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

4
Q

primary role of endothelial cells

A

line vascular system and important for drug distribution

5
Q

types of capillary endothelial cells

A

non-sinusoidal and non-fenestrated

non-sinusoidal-fenestrated

sinusoidal fenestrated (liver)

sinusoidal non-fenestrated (bone marrow)

6
Q

fenstrated endothelial cells

A

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

7
Q

major transvascular exchange for lipid-insoluble drugs

A

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

8
Q

aqueous filtration via structural pathway

A

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

9
Q

aqueous diffusion via aquaporins

A

aquaporins - water permeable only

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

10
Q

aquaglyceroporins

A

five subtypes

allows water and glycerol in

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

11
Q

AQP9

A

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

12
Q

Leishmaniasis

A

parasitic protozoa of genus leishmania

becomes drug resistant after mutation in aquaglyceroporin channels

button-like scar after recovery

13
Q

types of active transport

A

primary, secondary, and facilitated diffusion

14
Q

ABC transporters

A

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

15
Q

P-pg (also known as MDR1 or ABCB1)

A

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

16
Q

SLC transporter

A

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

17
Q

OATPs

A

SLC21/SLC0 - organic anion transporter

18
Q

OAT

A

SLC22 - the organic cation/anion/zwitterion transporter

19
Q

SLC6s

A

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

20
Q

SLC6A4

A

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

called selective serotonin reuptake inhibitors

ex. Prozac, Praxil, and Zoloft

21
Q

facilitated diffusion

A

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

22
Q

GLUT2

A

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

23
Q

transcellular transport

A

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

24
Q

transcytosis

A

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

25
Q

absorptive-mediated endocytosis

A

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

26
Q

receptor-mediated transport

A

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

27
Q

paracellular transport

A

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

28
Q

inter-endothelial cell junctions

A

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

29
Q

permeability of macula occludens

A

macromolecules as large as myoglobins and horseradish peroxidase

30
Q

vectorial transport

A

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

31
Q

Loratadine (Claritin) vs. Diphenhydramine (benadryl)

A

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

32
Q

Henderson-Hasselbalch equation

A

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

33
Q

chemical and physical properties of drugs in relation to transport

A

structural similarity to a natural compound

lipid vs. water solubility

34
Q

pKa and absportion

A

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

absorption of bases increases with decreasing pKa values

35
Q

ion trapping effect

A

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

36
Q

ibuprofen and ion trapping

A

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

37
Q

ion trapping and excretion

A

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