Lecture 4 - Protein Binding Concepts

Question 1

(T/F): Cb = C = Cu

Answer 1

False. Total concentration, concentration in blood and unbound concentration are different from one another, as the affinity of drug to proteins/blood cells in the various compartments is different.

Question 2

How to calculate Vu?

Answer 2

A (amount of drug in body at equilibrium)/ Cu (unbound concentration of drug)

Question 3

What can you say about the relationship between fraction unbound in plasma and tissues and the volume of distribution?

Answer 3

Drugs with a high fraction unbound in plasma and tissues (e.g. caffeine) have comparable volumes of distribution in blood, plasma and tissues.

Conversely, drugs with low binding affinity to plasma and tissues will have varying levels of volume of distribution in blood, plasma and tissues.

Question 4

What are the roles in plasma protein binding?

Answer 4

physiologic standpoint- plasma proteins serve as mobile carriers of hormones and micronutrients.
» prevents metabolic inactivation and excretory removal during transit through the circulation.
» selective delivery to the effector sites via specialised uptake transporters

for drugs and xenobiotics - plasma proteins usually:
» restrict diffusional uptake into target sites and eliminating organs
» therapeutic effects are better correlated with Cu than Cb or C.

Question 5

What does the free drug effect tell you?

Answer 5

That unbound, rather than bound concentration, is more important in therapeutics.
fu = Cu/C
fu and Cu can be independent from one another, but C is dependent on fu and Cu.

Question 6

What are the drug-protein binding characteristics of acidic and basic drugs?

Answer 6

Acidic drugs (e.g. NSAIDS, coumarin anticoagulants, anticonvulsants) bind exclusively to albumin, whereas basic drugs have a selective affinity for alpha-1 glycoprotein, but also bind to albumin and lipoproteins.

Question 7

What are some examples of inter-individual variations?

Answer 7

1. Variation in drug-protein affinity (due to genetic variants or mutations)
2. Variation in circulating level of proteins (due to disease)
3. Drug-drug interactions (displacement of binding, induction of alpha-1-AGP, acylation of albumin).

Question 8

What causes induction of alpha-1-glycoprotein?

Answer 8

disease states - uremia, inflammatory diseases, trauma and cancer, as well as
drug-drug interactions.

Question 9

What are some concepts from Scatchard Model and Fractional Binding?

Answer 9

fu = 1/(1+Ka.fup.Pt)
as Pt increases, fu decreases.
for drugs given at therapeutic concentration, if Pt remains constant, so will fu.

Question 10

How do you calculate new fu for drugs with small fu?

Answer 10

fu’ = fu x Pt/Pt’

Question 11

What is the effect of fu on V?

Answer 11

for drugs with a small V, change in fu results in a minimal change in V.
for drugs with a large V, changes in fu results in a large change in V.

Question 12

What are some concepts from the Gibaldi and McNamara Model?

Answer 12

V= Vp + Vt.(fu/fut)

1. If only unbound drug can transverse membrane barriers, change in plasma protein binding of drug is expected to alter extravascular distribution and its apparent volume of distribution.
2. Apparent volume of distribution V increases, when fu increases, and V decreases, when fut increases.
3. Vt and fu can be determined and fut estimated depending on Vt. Vt can be less than 39L if drug cannot access the entire TBW.
4. Model does not account for active transport processes that would maintain unbound concentration gradients between some tissue fluid and plasma water.

Question 13

What are some concepts from the øie and tozer model?

Answer 13

• Recognises that albumin and other plasma proteins are present in interstitial fluid.
• Drugs that have a smaller volume of distribution are more tightly bound to plasma proteins, and are largely acidic drugs like NSAIDS.
• Can be used to estimate volume of distribution for drugs with both a large and small volume of distribution.

Question 14

What does the “tug-of-war” for the drug between plasma and tissue proteins explain for acidic and basic drugs?

Answer 14

Acidic drugs tend to have small volumes of distribution (<1L/kg) due to their high affinity for plasma albumin, and low binding affinity for tissue proteins.

Basic drugs tend to have large volumes of distribution (>1L/kg) despite comparable affinity for plasma proteins because of extensive tissue protein binding and other sequestration mechanisms.

Question 15

(T/f): unbound concentration, Cu, is insensitive to change in plasma protein binding.

Answer 15

True

Question 16

What does statement 15 mean clinically?

Answer 16

• The increase in free drug concentration is generally transient as a result of redistribution and increased clearance. fu will be higher and total plasma concentration lower, but free drug concentration returns to original value and effect stays the same.
• dose adjustment should consider pharmacokinetics based on Cu.