Drug Distribution - 2 Flashcards
Passive diffusion
- ___ concentration
gradient - ___ saturable
- Most common
- down
- not
Paracellular transport is for hydro___ , ___ (size) molecules
hydrophilic, small
goes in between cells (not through their membrane)
Facilitated diffusion
- ___ concentration gradient
- Via ___
- Saturable
- ___ (OATP)
- Drug example: ___
- down
- carriers
- organic aniontransporting polypeptides
- pravastatin
Active transport
- ___ concentration gradient
- Via ___
- Uses ___ (energy)
- Saturable
- P- ___
- Drug example: ___
- against
- transporter
- ATP
- glycoprotein
- Vincristine (chonky)
P-glycoprotein will kick drugs out at the cell sing ATP
T or F: Carrier-mediated transport is saturated at high drug concentrations
true
Factors determining diffusion
molecular ___
* poor permeability for ___ molecules
lipo___
* poor permeability for ___ molecules
- size, large
- lipophilicity, hydrophilic
definition
LogP
Indicator of compound lipophilicity. The larger, the more lipophilic
Factors determining diffusion
Charge
* poor permeability for ___ molecules
charged
Must be unionized to pass membrane
Perfusion-rate limitation
For lipophilic compounds:
Rate-limiting step for drug distribution is…
the amount of blood carrying drugs away
Permeability-rate limitation
Hydrophilic compounds: Rate-limiting step for drug distribution is …
the slow rate of drug passing the cell membrane
Rate-limiting factor in tissue distribution
T or F: lipophilic compounds are permeability rate limited
False; hydrophilic compoounds are permeability rate limited. lipophilic compounds are perfusion-rate limited
Rate-limiting factor in tissue distribution
T or F: lipophilic compounds are permeability rate limited
False; hydrophilic compoounds are permeability rate limited. lipophilic compounds are perfusion-rate limited
Rate-limiting factor in tissue distribution
T or F: lipophilic compounds are permeability rate limited
False; hydrophilic compoounds are permeability rate limited. lipophilic compounds are perfusion-rate limited
Rate-limiting factor in tissue distribution: Example
Propofol
* General anesthesia-inducing agent
* Nonpolar lipophilic compound (logP 3.79)
* Distribution is perfusion-rate limited
Q: Which of the following two tissue would show faster propofol distribution?
The brain
What are the major drug binding plasma proteins?
- albumin
- a1-acid glycoprotein
- lipoproteins
Albumin
- The most abundant plasma protein ( ___ % of human plasma proteins)
- Produced in the ___
- Binds free ___ acids, hormones and weakly ___ (anionic) drugs
- Main function is to maintain the ___ pressure of blood
- Serum levels are decreased in ___ and ___ diseases
- 50%
- liver
- fatty, acidic
- oncontic
- liver, kidney
α1 -Acid glycoprotein (AAG) and lipoproteins
- Also known as ___
- Produced in the ___
- Binds primarily weakly ___ (cationic) drugs such as tertiary and quaternary amines
- Serum levels ___ during acute phase reaction, e.g., inflammation and burns
- Serum levels are ___ in liver and kidney diseases
- orosomucoid
- liver
- basic
- increase
- decrease
Lipoproteins
- Lipophyllic protein and/or a complex of ____ and ___
- Includes ___ and ___
- Binds ___ drugs.
- Altered in some disease states, including ___ disease.
- proteins and lipids
- HDL and LDL
- lipophilic drugs
- heart
Free drug hypothesis: Effects of protein binding on drug transport
Only ___ drug can exit capillaries to reach extravascular sites of
action, cross cell membrane via diffusion, and bind to transporters
free (unbound)
Reversible nature of protein binding
T or F: Plasma protein binding of drugs is reversible
true
T or F: Free (unbound) drug concentrations are the same on both sides of the membrane at equilibrium
true
Plasma vs Blood
- In most PK studies, we measure drug concentrations in ____
- Plasma is the ___ component of blood, in which the blood cells are suspended (yellow colored)
- Plasma makes up about ___ % (50-60%) of total blood volume
- Plasma contains many vital proteins including ___ , ___ and ___
- plasma
- liquid
- 55%
- fibrinogen, globulins, and albumin
Serum
- Blood is allowed to ___. Clotting occurs, and it settles at the bottom of the tube
- The ___ fluid is called serum
- Serum is devoid of blood cells, ___ , and ___ factors
- Serum contains plasma proteins, such as ___
- coagulate
- supernatant
- fibrin, clotting
- albumin
Unbound fraction (fu)
Total drug concentration (C): Measure drug concentration after sample processing to ___ both protein-bound and free drug molecules
Free drug concentration (Cu): Measure drug concentration after sample processing to ___ protein-bound drug molecules
Unbound fraction (fu) = Cu/C
- extract
- exclude
Ultrafiltration method
True/False: In the example, the measured drug concentration reflects “total” drug concentration (i.e., C, not Cu)
True
True/False: In the example, the measured drug concentration reflects “total” drug concentration (i.e., C, not Cu)
True
Determinants of Vd
What is the equation for this?
amount in the body = amount in plasma + amount outside plasma
Determinants of Vd
What equation reflects this?
Volume of distribution increases when fu is increased.
Volume of distribution decreases when fuT is increased.
Vd of propranolol ___ when fu is
increased due to ___ plasma
protein binding in patients with chronic hepatic diseases
- increases, decreased
Determinants of Vd: tissue binding
- Digoxin plasma protein binding is 25% ___
- Digoxin binds to cardiac Na+/K+ ___
- Digoxin has large Vd (7 L/kg) due to extensive ___ binding
- cardiomyocytes
- ATPase
- tissue
practice questions
T or F: Ionized compounds show poorer membrane permeability than un-ionized compounds
true
practice questions
T or F: Lipophilic compounds tend to show greater membrane permeability
true
practice questions
T or F: Lipophilic compounds tend to show permeability rate-limited distribution
False; perfusion
practice questions
T or F: Decreased plasma protein binding of high protein-bound drugs will likely increase Vd
true
T or F: Vd is expected to be small for a drug that exhibits strong binding to tissue components
false
