Protein Binding Principles

Question 1

What is distribution?

Answer 1

reversible movement of drug between the systemic circulation and the tissues of the body

Question 2

Differentiate between limited tissue distribution and high tissue distribution.

Answer 2

limited tissue distribution:
-only some drug leaves the circulatory system
-drug Cp is high
high tissue distribution:
-a lot of drug leaves the circulatory system
-drug Cp is low

Question 3

What is protein binding?

Answer 3

the non-covalent, reversible interaction of a drug with a protein to form a protein-drug complex

Question 4

What are examples of drug-protein interactions relevant to PK and PD?

Answer 4

drug transporter
-forms drug-transporter complex
-drug is transported across the membrane
drug metabolizing enzyme
-forms drug-enzyme complex
-drug is metabolized to metabolite(s)
plasma protein
-forms drug-plasma protein complex
-drug is bound to plasma protein
pharmacological receptor
-forms drug-receptor complex
-drug produces therapeutic effect or toxic effect

Question 5

What step of ADME do drug-protein interactions occur?

Answer 5

any step
or during the response

Question 6

What is the basic tenet of pharmacology?

Answer 6

pharmacological response is related to the unbound (free) drug concentrations at the receptor site

Question 7

What is the influence of PK on the basic tenet of pharmacology?

Answer 7

PK determines the availability of a drug at its receptor site following a dose administration
protein binding interactions influence concentration of free drug at pharmacological receptor site

Question 8

What is the importance of protein binding on drug effect?

Answer 8

only unbound drug can:
-bind to its site of action and exert an effect
-be distributed to the tissues by passive diffusion or by transporters
-be excreted by the kidney or undergo metabolism to be eliminated

Question 9

What is the general mathematical model relationship describing drug-protein interactions?

Answer 9

Y=aX/(b+X)
Y: rate
a: capacity term
b: affinity term
X: drug concentration

Question 10

What are the terms used to describe affinity for binding?

Answer 10

Kd, Km, EC50
-higher the affinity, the lower their value
-units of concentration
-concentration required to reach half maximal capacity

Question 11

What are the terms used to describe capacity for binding?

Answer 11

nP, Tmax, Vmax, Emax
-depends upon the total number of binding sites (total protein conc, number of binding sites/protein)
-saturable (finite number of binding sites, at saturation as drug conc increases–>decrease in the fraction of drug bound to protein)

Question 12

What are the factors influencing drug-protein binding?

Answer 12

drug
-PC properties, concentration
protein
-quantity (capacity), PC nature
affinity
-magnitude of dissociation constant
drug interactions
-competitive binding, alteration of protein that affects affinity
pathophysiological condition
-influences: quantity of protein, binding affinity

Question 13

What is the equation for drug-plasma protein binding?

Answer 13

Cb=nPCu/(Kd+Cu)
Cb: conc of bound drug
Cu: conc of unbound drug
np: total binding capacity
Kd: dissociation constant (affinity)

Question 14

Which drugs bind plasma proteins?

Answer 14

lipophilic drugs
polar drugs show negligible binding to plasma proteins

Question 15

What is fu(b)?

Answer 15

fraction unbound in plasma
-indicates the relationship between unbound drug concentration in the plasma with total drug concentration in the plasma
-unitless parameter–>number between 0-1
-a constant value until saturation where fu(b) decreases with further increase in drug concentration

Question 16

What does a low fu(b) indicate?

Answer 16

high concentration of drug is bound to plasma protein

Question 17

What are the types of plasma binding proteins?

Answer 17

albumin
alpha1-acid glycoprotein (AAG)
cortisol binding globulin (transcortin)
lipoproteins

Question 18

Describe albumin.

Answer 18

principal binding plasma protein
-multiple binding sites
55-60% of extracellular albumin is outside the vascular compartment
acidic lipophilic drugs bind more strongly and extensively than basic lipophilic drugs

Question 19

Describe AAG.

Answer 19

important plasma protein
lower concentration vs albumin
acute phase reactant protein
-conc markedly increases with inflammatory conditions, malignant disease, stress
binds basic drugs

Question 20

Explain the rate of protein binding when Cp is high and when Cp is low.

Answer 20

when Cp is high, you get saturation of protein=constant rate of binding
when Cp is low, you get a rate of binding proportional to Cp

Question 21

What does Cb depend on?

Answer 21

capacity: total protein concentration
affinity: dissociation constant
unbound concentration

Question 22

What is the significance of plasma protein binding?

Answer 22

only unbound drug exerts pharmacological effect
important determinant of Vd
most elimination mechanisms require free drug
buffering/solubilizing effects
-assures solubility of poorly aqueous soluble drugs
pathophysiological conditions affect capacity and affinity

Question 23

Why are we concerned when drug is extensively bound to plasma protein?

Answer 23

extensive drug binding to plasma protein may mean small Vd
binding is clinically significant when fu(b) is <0.2
possible drug displacement interactions
potential source of nonlinear PK

Question 24

Why is binding considered to be clinically significant when fu(b) is <0.2?

Answer 24

changes in binding (drug-drug or drug-disease interaction) might cause significant changes in fu(b) and therefore might be therapeutically important