E1 L2: Drug Distribution Flashcards
Passive diffusion properties
Drug passes down concentration gradient
Not saturated
Most common
Transcellular junctions
Cross lipid bilayer (go through)
Paracellular diffusion
Go between (for hydrophilic small molecules)
Facilitated diffusion
Down concentration gradient
Via carriers
Saturable
E.g. Organic anion transporting polypeptides (OATP)
Active transport
Against concentration gradient
Via transporter
Uses ATP (energy)
Saturable
Ex. P-glycoprotein
Passive diffusion graphed
Increases linearly with concentration
Carrier mediated transport graphed
Curved - too much drug in system = saturation (saturated at high drug concentrations)
Passive diffusion:
Involvement of a protein channel or transporter?
Saturable?
Direction?
ATP Use?
No
No
High to low conc
No
Passive FACILITATED diffusion:
Involvement of a protein channel or transporter?
Saturable?
Direction?
ATP Use?
Yes
Yes
High to low
No
Active Transport:
Involvement of a protein channel or transporter?
Saturable?
Direction?
ATP Use?
Yes
Yes
Low to high
Yes
Factors determining diffusion
Molecular size - poor permeability for large molecules
Lipophilicity - poor permeability for hydrophilic molecules
Indicator of compound lipophilicity
The larger, the more lipophilic (hydrophobic)
LogP
Best permeability has..
Small MW
Large LogP
Factors determining diffusion
Molecular size
Lipophilixty
Charge
Q: T/F: Salicylic acid will exhibit better crossing through the lipid bilayer at higher pH (ie. in basic condition)
False - higher pH = ionized= worse permeability
Perfusion rate limited
Only limiting factor- rate of blood flow
Permeability rate limited
Do not cross membrane readily
Perfusion rate limitation: hydrophobic or hydrophilic?
Hydrophobic (rate of blood flow)
Permeability rate limitation: hydrophobic or hydrophilic?
Hydrophilic (does not readily cross membrane)
Perfusion vs. Permeability rate limited graphed
Perfusion: High concentration (more lipophilic)
Permeability (low line)
Q: which of the following would have a faster propofol distribution (nonpolar lipophilic - LOG P = 3.79)
Brain: perfus rate: 0.5
Muscle: Perfus rate 0.025
Brain - Compound is perfusion rate limited
Small compound that distributes perfusion rate limited
Major drug binding plasma proteins
ALBUMIN
a1-acid glycoprotein
Lipoproteins
Most abundant plasma protein
Produced in the liver
Binds FFA, hormones, and weakly acidic (anionic) drugs
Main function - maintain oncotic pressure of blood
Serum levels decreased in liver and kidneys
Albumin
AKA orosomucoid
Produced in liver
Binds primarily weak basic (cationic) drugs such as tertiary and quaternary amines
Serum levels increase during acute phase reaction, e.g. inflammation and burns
Serum levels are decreased in liver and kidney diseases
a1-Acid glycoprotein (AAG)
Lipophyllic protein and/or a complex of proteins and lipids
Includes HDL and LDL
Binds hydrophobic drugs
Altered in some disease states, including heart disease
Lipoproteins
Free drug hypothesis:
Only free drug exists capillaries to reach extravascular sites of action
Only free (unbound) drug crosses cell membrane via diffusion
Only free (unbound) drug binds to transporters
T/F: Plasma protein binding of drugs is reversible
True
Plasma makes up how much of the total blood volume?
50%
Coagulated blood that settles at the bottom of the tube
Serum
Serum is devoid of
Blood cells
Fibrin
Clotting factors
Serum contains
Plasma proteins (like albumin)
Unbound fraction
Free drug concentration/Total concentration
Determinants of Vd
V = Vp + VTW * fu/Fut
Q: T/f: Ionized compounds show poorer membrane permeability than unionized compound
True
Q: T/F: Lipophilic compounds tend to show greater membrane permeability
True
Q: T/F: Lipophilic compounds tend to show permeability rate-limited distribution
False (lipophilic=diffusion rate limited)
Q: T/F: Decreased plasma protein binding of high protein bound drugs will likely increase Vd
True
Q: T/F: Vd is expected to be small for a drug that exhibits strong binding to tissue components
False - (goes up)
