Drug Transport Flashcards
three factors that are important in controlling durg transport across cell membranes
membrane as barriers
specialized transport mechanisms
physico-chemical properties of drugs
three important cell types that influence drug transport across cell membranes
epithelial cells
endothelial cells
cells at site of action
primary role of epithelial cells
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
primary role of endothelial cells
line vascular system and important for drug distribution
types of capillary endothelial cells
non-sinusoidal and non-fenestrated
non-sinusoidal-fenestrated
sinusoidal fenestrated (liver)
sinusoidal non-fenestrated (bone marrow)
fenstrated endothelial cells
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
major transvascular exchange for lipid-insoluble drugs
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
aqueous filtration via structural pathway
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
aqueous diffusion via aquaporins
aquaporins - water permeable only
aquaglyceroporins - water and glycerol permeable as well as molecules less than 150 Da
aquaglyceroporins
five subtypes
allows water and glycerol in
drugs that are highly water soluble and have low membrane partition coeffiicents can also take these routes
AQP9
an aquaglyceroporin that allows ater, glycerol, urea, carbamides, purines, pyrimidines, and metallic ions to pass through
Leishmaniasis
parasitic protozoa of genus leishmania
becomes drug resistant after mutation in aquaglyceroporin channels
button-like scar after recovery
types of active transport
primary, secondary, and facilitated diffusion
ABC transporters
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
P-pg (also known as MDR1 or ABCB1)
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
SLC transporter
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
OATPs
SLC21/SLC0 - organic anion transporter
OAT
SLC22 - the organic cation/anion/zwitterion transporter
SLC6s
also plays an important role in terminating the transmitter action in the CNS by uptake of transmitters into the terminal and glial cells
SLC6A4
serotonin transporter - a target for a major class of antidepressant drugs
called selective serotonin reuptake inhibitors
ex. Prozac, Praxil, and Zoloft
facilitated diffusion
a form of SLCs that allow solutes to flow downhill with their electrochemical graidents
GLUT2
SLC2A2 - important in transferring glucose intoo skeletal muscles (via facilitated diffusion), which is increased in response to insulin
transcellular transport
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
transcytosis
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
absorptive-mediated endocytosis
polycationic peptides bind to the negative charges on cell membranes to initiate endocytosis
receptor-mediated transport
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
paracellular transport
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
inter-endothelial cell junctions
depending on the location, endothelial cells form different junctions form a very tight junction to macula occludens, or loose junctions
permeability of macula occludens
macromolecules as large as myoglobins and horseradish peroxidase
vectorial transport
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
Loratadine (Claritin) vs. Diphenhydramine (benadryl)
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
Henderson-Hasselbalch equation
log([protonated form]/[unprotonated form]) = pKa - pH
chemical and physical properties of drugs in relation to transport
structural similarity to a natural compound
lipid vs. water solubility
pKa and absportion
at a fixed pH, absorption of acidic drugs increases with increasing pKA values
absorption of bases increases with decreasing pKa values
ion trapping effect
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
ibuprofen and ion trapping
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
ion trapping and excretion
accelerated excretion can be achieved if the drug is in the ionized form when in the urine
