Pharmacokinetics 2: Drug Distribution Flashcards
How are drugs distributed?
Tranditional view: Passive diffusion and strongly influenced by its physicochemical properties.
Binding to proteins in plasma vs tissues is important and blood flow plays a vital role in exposing tissues to circulating drugs.
Emerging view is that drug transporters strongly regulate drug distribution:
SLC transporters move drugs between compartments into tissues. ABC transporters mainly move drugs out of tissues.
What factors influence drug distribution?
Blood flow to particular tissues.
Size of tissues
Binding to plasma proteins
Binding to tissue proteins
Permeability of tissue membranes
Presence of protein transporters on membrane of target tissues.
Where do oral drugs go immediately after absorption?
The liver
Which tissues get more drug?
More well-perfused tissues such as lungs, liver and kidneys.
How do drugs move through capillary walls?
Through fenestrations on capillaries (average gap of 4nm). Most drugs are smaller than this.
What does drug penetration ensure?
Ready access to drug receptors on cell surfaces.
What is the main barrier to substance exchange by diffusion?
The basal membrane.
What molecules can pass easily through basement membrane?
Molecules smaller than 10 kDa
What replaces fenestrations in brain capillaries?
Tight junctions
What influences where around tissues the drug accumulates?
Their mass, polarity, and lipophilicity
Where do drugs accumulate in tissues?
Intracellularly
Within interstitial fluid
or in Fat
What does the volume of distribution tell us?
It provides information about how the drug is distributed if we assume the body behaves as one homogenous compartment.
What is the formula for V distribution?
Dose/plasma concentration
What happens in reality to drug distribution?
Its distribution would usually reflect plasma concentrations within the body.
What is the one compartment model of drug distribution?
Drug is evenly distributed throughout the body.
What is the two-compartment model of drug distribution?
Drug in blood stream is lost to another peripheral compartment
What does Vdist tell us?
It tells us how the drug behaves during the distribution phase.
A high Vdist means the drug accumulates in the tissues rather than the blood
A low Vdist means the drug accumulates in the blood rather than in tissues.
How is water distributed in the body?
4.5 - 5L in blood [3L plasma 2L within blood cells]
12L interstitial water
27L intracellular water.
Plasma + interstitial water make up 15 L extracellular water
What must occur for a drug to stay within the plasma?
Either it is very big or it has strong plasma protein binding properties
Where do hydrophilic and hydrophobic drugs tend to penetrate?
Within interstitial fluid as lipophilicity increases they can penetrate intracellular space and tissues.
Highly lipophilic drugs can penetrate fat and muscle
When is a high volume of distribution useful?
When trying to access tissues that are hard to access such as muscles and skin.
When is a low volume of distribution useful?
When trying to keep drug within the blood plasma
What is the concentration of plasma protein on average in plasma? What is the function of plasma protiens?
Plasma contains 60 - 80g protein/L. Plasma proteins serve as carriers for natural compounds plus many drugs.
What plasma protein do acidic drugs bind to?
Albumin
What plasma protein do basic drugs bind to?
Alpha1-glycoprotein.
Can drug bound to transport protein carry out its function? What does this mean?
No it must be free (unbound). Higher doses are needed for therapeutic effect.
What undesirable outcome can occur from plasma protein binding?
Competition between drugs may cause DDIs
What does transport protein binding do to drug clearance?
It slows clearance down
Which drugs bind to plasma proteins?
Lipophilic drugs (i.e drugs with high logP)
How big is albumin?
65 kDa monomer
What are tissue proteins important for?
They can bind drugs at certain concentrations at equilibrium
Examples of drug-binding tissue proteins:
Albumin
Ligandin (liver kidneys intestines)
Myosin and actin
Melanin
What proportion of CNS potential drugs fail to penetrate BBB?
98%
Which drugs can be stored in fat?
Only highly lipophilic drugs
Which drugs can be present for a long time in fat? What does this mean?
Only highly lipophilic drugs (eg. THC and anabolic steroids)
Drugs can accumulate in fatty tissue and this can result in complications of high drug concentrations.
Which common drugs have high fat partitioning?
Volatile anaesthetic agents
How does the liver detoxify so many foreign material?
It has many diverse influx receptors that allow uptake of drug.
Which transporters are important for metformin transport into the liver? What happens in KO mice of this receptor?
OCT1/2, they had lower Vdist of metformin meaning more metformin was present in the blood.
Where can drugs accumulate after absorption?
A) Transport protein binding
B) Tissue protein binding
C) Brain penetration
D) Partitioning into fat
