Plasma Protein Binding (PK3) Flashcards
What is plasma protein binding?
Plasma protein binding refers to the degree to which drugs attach to plasma proteins within the blood.
When considering drug distribution within the blood stream, the drug molecule can..?
- bind within or on the surface of the Red Blood Cells (RBC)
- bind plasma proteins
- be associated to plasma water
What are the 4 main classes of plasma proteins? what levels are they present in?
- Albumin (35-50 g/L concentration, most abundant protein in plasma);
It has a large drug binding capacity having a Molecular weight of 67,000 Dalton. - α1- acid glycoprotein is present in lower concentration in plasma than albumin (0.4-1
g/L concentration) - Lipoproteins (variable amount)
- Globulins
What can bind to albumin?
Both endogenous compounds (such as fatty acids, bilirubin) as well as drugs can binds to albumin
What do each domain of albumin contain?
Sudlow Site I, also known as warfarin binding site
Sudlow Site II, also known as benzodiazepine
binding site
* Based on early agents used in experiments to
analyse these binding site.
* As there are three identical domains making up the
human albumin molecule, that gives a total of six
binding sites per albumin.
* Acidic compounds tend to bind to albumin
What kind of drugs bind to α1 -acid glycoprotein
Basic drugs often bind to α1 -acid glycoprotein (e.g., imipramine, lidocaine, propranolol, quinidine)
What are the different types of Lipoproteins + what they can bind to?
Different types: VLDL, HDL (High density lipoprotein), LDL (Low density
Lipoproteins), Chylomicrons
They can bind a wide range of compounds
Acidic compounds: Diclofenac
Neutral compounds: Cyclosporin A
Basic: chlorpromazine
More than one plasma protein is usually involved in drug binding, what order are they from most to least?
The extent or order of binding of drug to plasma proteins is:
Albumin> α1- acid glycoprotein >Lipoproteins> Globulins
What are the intensity of binding interactions?
- Binding interactions between drugs and plasma proteins are generally reversible.
- Reversible interaction involves weak chemical bonds such as:
o hydrogen bonds
o Hydrophobic bonds
o Van der Waal’s forces, - Mostly they are non-specific interactions
- The process is saturable: once all the binding sites are occupied no more drug can
bind
When will a plasma protein to drug bond be permanent?
if the bonding is covalent and is often
a reason for carcinogenicity or tissue toxicity of the drug
Describe the free drug hypothesis?
here is a dynamic equilibrium of drug between bond and unbound states.
The drug-plasma protein is too large to cross the capillary membranes and reach the
tissues. Drug bound to plasma protein remains within the blood compartment.
A drug that binds to plasma protein diffuses less efficiently than a drug that doesn’t.
Only unbound compound is available for distribution in the tissues (the liver, the kidney
and where the drug should have the pharmacological effect).
free drug hypothesis in terms of plasma, liver, kidney + other tissues
PLASMA: equilibrium between unbound and bound fraction of the drug. Only the unbound
fraction can cross the capillaries and reach the tissues.
LIVER: Once in the liver, the unbound fraction can be recognised by the enzymes that
catalyse the metabolism.
Free drug hypothesis
KIDNEY: Once in the kidney, only the free drug can
be excreted.
OTHER TISSUES: Once the target tissue is reached,
the unbound fraction con interact with the drug target
(either a protein, enzymes, etc) and produce the
pharmacological responce.
% of drug in plasma unbound based on what drugs? show
Drugs with a negligible plasma protein binding (fu=100%):
- Atenolol, metformin
Drugs with a consistent plasma protein binding (fu=1%):
- Warfarin, ibuprofen
What do each % of unbound drug to plasma mean? 50 - >99?
0-50% bound = negligible effect of plasma protein binding
50-90% = moderate plasma protein binding
90-99% = high plasma protein binding
e.g., Phenytoin, propranolol, sodium valproate
>99% = very high plasma protein binding
e.g., Warfarin, furosemide, heparin, diazepam
What does free fraction ( fu) take into consideration?
Free fraction (fu) takes in consideration the unbound fraction; % of plasma protein
binding takes in consideration the bound fraction.
All the drugs with high % plasma protein binding will have a small free
fraction (fu) and vice versa.
How can we track plasma proteins in the bodY?
plasma sampling
What is plasma sampling?
Plasma sampling allows to measure
the total drug concentration (i.e. the
sum of the bound and unbound drug) within the blood important for clinical purposes.
A follow-up calculation is made to
determine the free drug concentration
(fu equation).
what factors influence plasma protein binding?
- Plasma protein composition
Intersubject variability (due to genetics and environmental factors)
Obesity - Age of the patient
Neonates: Low albumin content -> more free drug
Elderly people: Low albumin content -> more free drug
what factors influence plasma protein binding? (physiochemical only)
- Physiochemical characteristics of the drug
An increase in lipophilicity increases the extent of binding.
Blood is primarily made of water; If a drug is lipophilic drug, it is not soluble in water and
the drug can only move in the blood stream bond to plasma proteins
The structural feature of the drug will inform which component is more involved in plasma
protein binding: - acid compounds bind mainly albumin
- basic compounds primarily α1- acid glycoprotein
what factors influence plasma protein binding? (disease states only)
- Disease states: the amount of plasma protein available for binding changes during disease state
Liver and renal diseases as well as burns decreases albumin levels (as albumin is produced by the liver)
Inflammatory diseases and trauma cause increase of 2- to 5-fold the glycoprotein concentration.
What is displacement?
Displacement is the reduction in the binding of a drug to a macromolecule, usually
a plasma protein, caused by competition of another drug, the displacer, for
common binding site(s). The result is a rise in fu.
Drug-drug interactions regarding plasma protein binding have clinical relevance only when?
Highly bound drug (>90% plasma protein binding)
Drug with narrow therapeutic index
Drug is given IV (intravenously)
Drug with high-clearance
how do high vs low plasma protein binding align in distribution?
High plasma protein binding (low free drug) will limit the distribution of the drug as
well as the clinical response.
Low plasma protein binding align with wide drug distribution.
What is sustain release?
The complex of drug- plasma protein in the blood acts as reservoir and continuously supply
the free drug.
Significance plasma protein binding
Systemic solubility of drug?
Lipoproteins act as vehicle for hydrophobic drugs like
Steroids, heparin and oil soluble vitamins
