Drug Distribution Flashcards
What is drug distribution?
The post-absorptive transfer of drug from one location in the body to another
Why isn’t 1COM adequate enough to describe distribution?
Assuming drug distribution is instantaneous at t=0
What is best model to describe distribution?
Multi-compartmental model
What are the 2 components of drug distribution?
Rate and extent
What is rate of drug transfer?
- How fast the distribution phase lasts
- Estimated by distributional clearance and inter-compartmental clearance or rate of perfusion (Q)
How is the extent of drug distribution assessed?
Volume of distribution
What is the 2-stage process of drug distribution?
- Presentation of the drug to the tissue by the blood
- Diffusion or uptake of drug from the blood to the tissue
What limit the overall rate of distribution?
The slower of the steps in the 2-stage process
Describe perfusion-controlled drug distribution?
- Drug molecules are presented to tissues by specific arterial blood flow to them
- The rate of drug presentation is expressed as rate of tissue perfusion (Q)
- The unit of tissue perfusion is describe by the volume of blood delivered to the tissue per unit time (mL/min)
What does it mean to be perfusion-controlled?
Drugs that tend to distribute less to tissues because of lower perfusion rate
What is an example of perfusion-controlled drug distribution?
In patients with congestive heart failure
What is hydrostatic pressure?
Creates the pressure gradient between the arterial end entering the tissue and the venous capillaries leaving the tissue
What is the hydrostatic pressure responsible for?
Penetration of water-soluble drugs into spaces between endothelial cells and possibly into lymph
Describe diffusion-controlled drug distribution?
- Once the drug molecules arrive close to tissue site, they rapidly diffuse into interstitial fluid of capillaries
- Further diffuse from interstitial fluid across the tissue membrane to be in the tissue, driven by passive diffusion across the epithelial membrane
What is the difference between penetration of lipid-soluble and water-soluble?
L: penetrate most membrane barriers and distributes to fat tissues
W: doesn’t distribute well into fat tissues
What does it mean to be diffusion-controlled or permeability-controlled?
When drug distribution into the tissue is controlled by slow diffusion of drug molecules across the tissue membrane
What is an example that causes diffusion-controlled drug distribution?
During inflammation
What dose the distributional half-life represent?
The time required for plasma concentration to decline by 50% during the distribution phase
What is distributional half-life used for?
To determine how long a drug takes to distribute from central to peripheral compartment
What is the equation associated with distributional half-life?
t1/2,a = 0.693/a
What is tss?
Time to reach steady state when the rate of distribution (input) = rate of redistribution (output)
What is the equation associated with tss?
tss = (t1/2,a) * 5
Define extent of drug distribution?
The relative distribution of drug molecules between plasma and rest of the body
How much blood is in an average healthy adult (70kg)?
5L
How much plasma is in an average healthy adult (70kg)?
3L
How much interstitial water is in an average healthy adult (70kg)?
12L
How much intracellular water is in an average healthy adult (70kg)?
27L
What are the physiological fluid volumes in which drug is distributed to?
- Plasma: 3L
- Extracellular (15L) = Plasma (3L) + Interstitial water (12L)
- Total body fluid (42L) = Extracellular (15L) + Intracellular (27L)
Where is drug molecules distributed once reaching systemic circulation?
The volume of plasma water
What are the factors that determine the extent of drug distribution beyond plasma water?
- Physiochemical properties of the drug
- Permeability characteristics of the membrane
List physiochemical properties of the drug?
- Increased lipid-solubility -> favors movement of drug outside plasma
- Decreased molecular size -> favors movement of drug outside plasma
- Increased protein binding -> restricts movement of drug outside of plasma
Describe what happens is drugs distribute only in plasma (average human: 70kg)?
Vd = (3L)/(70kg) = 0.04L/kg
Where are most drugs distributed to?
Volume of extracellular fluid (15L)
Why do most distribute in extracellular fluid?
Epithelial membrane of capillary cells is veery loose and permits passage of even polar and protein molecules
Describe what happens is drugs distribute in extracellular fluid (average human: 70kg)?
15L/70kg = 0.2 L/kg
Where would drug distribute after extracellular fluid?
Intracellular fluids of the tissue
What factors effects a drug’s ability to penetrate individual cell membrane?
Physiochemical properties: small, lipophilic drug molecules penetrate biological membranes easily and distribute throughout the total body water (42L)
What prevents drugs from penetrating cell membranes?
Unless there are specialized uptake transporters, polar and larger molecules are unable to pass cell membranes by passive diffusion
Describe what happens is drugs distribute in total body water (average human: 70kg)?
42L/70kg = 0.6L/kg
How is a drug able to distribute beyond total body fluid?
Depends on lipohilicity and tissue structure binding affinities, they will have a greater 42L of Vd
What is the average Vd in a average human?
> 0.6L/kg
What is apparent volume of distribution?
A hypothetical volume of fluid required to contain the total dose of a drug in the body at the same concentration as that present/measured in plamsa
What is the equation for Vd?
Vd = Amount in body/ concentration in plasma
When is Vd constant?
Normal physiologic and health conditions
What affects Vd?
- Pathological condition that disturb body volume
- Plasma protein concentrations and binding
- Tissue binding
- Body weight
What is used to estimate the apparent Vd?
Compartmental PK models
Why would the extent of Vd be great than the total body fluid?
The available physiological volumes and drugs’ properties drive the extent of the drugs distribution
What is the drug distribution in 1COM?
- Instantaneous in central compartment
- Not assumed to move to any peripheral compartment
- Vd = Vc
What is the drug distribution in 2COM?
The drugs will move from the central compartment to peripheral compartments
What is the purpose of measuring 3 different Vd values?
Plasma concentration-time curve of drugs after a single IV bolus are characterized based on the time they occur after the dose
What are the 3 Vd?
Vc, Css, Vb
Identify the components of the graph
A: Vb
B: Vss
C: Vc
D: tss
E: Distributional equilibrium
F: pseudodistribution equilibrium
Why is Vss important?
Physiological relevance reflecting the extent of drug distribution from the plasma pool into tissues
What are the approaches of estimating Vss?
- Based on 2COM system
- Based on the extent of drug binding to plasma proteins with the actual plasma volume and the extent of drug binding to tissue proteins with the actual tissue volumes
How do you estimate Vss based on 2COM system?
Vss = Vc + Vp
How do you estimate Vss based on the extent of drug binding?
At equilibrium between the plasma and the tissues, the extent of drug distribution depends on its binding to plasma proteins, blood cells, tissue structures, and the actual total volumes of plasma and tissues
How can Vd exceed total body volume?
Drug binds to peripheral tissue structures
What can a drug bind to when in the plasma and tissue?
Reversibly bind to proteins and macromolecules
What are examples of plasma proteins susceptible to drug binding?
- Albumin
- Globulins
- a-1-acid glycoprotein
- Lipoproteins
What are examples of tissue structures susceptible to drug binding?
- Nucleic acid
- Ligands
- Calcified tissues
- ATP
What is the difference between bound and unbound drugs?
B: Can’t participate in the concentration gradient that drives the distribution
U: Drug diffuses outside of plasma
How much of plasma proteins are albumin?
55%
Where is albumin synthesized?
Liver
What happens if a drug has 90% plasma proteins binding?
- 90% of drug in plasma is bound to plasma proteins
- 10% is unbound and able to diffuse to tissues
What is distribution at steady-state during plasma protein binding?
- Free concentration in plasma = free concentrations in tissues
- Total concentration of drug (un + bound) in the plasma»_space;» total concentration of drug (un + bound) in the tissue
What causes small Vd values?
The strength of plasma protein binding restricts the distribution of such drug outside of plasma while concentrating it in the plasma
What happens if a drug has 90% binding to tissue structures?
- Large fraction of drug will bind to tissue structures and will be removed from participation in the diffusion gradient
- More and more drug will distribute to the tissues
When is steady-state of tissue drug binding?
- Free concentration in plasma = free concentrations in tissues, but
- Total concentration of drug (un + bound) in tissue»_space;» total concentration of drug (bound + un) in the plasma
What causes high Vd values?
The strength of tissue binding pulls the drug away from the plasma and concentrates it in the tissue
How can the amount of drug in body be separated?
Abody = Aplasma + Atissue
What is the fraction of drug in the plasma?
(fP) = Aplasma/Abody
or Vplasma/Vd
What is the fraction of drug in tissue?
(fT) = 1- Aplasma/Abody
How do you determine the amount of drug in the plasma?
Aplasma = Vplasma * Cplasma
How do you determine the amount of drug in the body?
Abody = Vd * Cplasma
How does unbound drug pass through to tissue?
Passive diffusion
How do you find undbound plasma concentration?
(Cu,P) = Cplasma * fu,plasma
How do you find unbound tissue concentration?
(Cu,t) = Ctissue * fu, tissue
How do you find Vd at steady state?
Vd,ss = Vplasma + Tissue (fu,p/fu,t)
