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Plasma drug protein binding. Update: 01:/07/2006. Biological relevance of drug binding. The binding of drug to plasma (and tissue) proteins is a major determinant of drug disposition (distribution)

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plasma drug protein binding

Plasma drug protein binding

Update: 01:/07/2006

biological relevance of drug binding
Biological relevance of drug binding
  • The binding of drug to plasma (and tissue) proteins is a major determinant of drug disposition (distribution)
  • Binding has a very important effect on drug dynamics since only the free (unbound) drug interacts with receptors
relevance of plasma and tissue protein binding
Relevance of plasma and tissue protein binding
  • From a biological point of view  YES
  • From a clinical point of view  NO
    • problem of drug interaction and displacement has been overestimated
slide6

Influence of drug binding on pharmacokinetic parameters

  • Distribution
  • Elimination

o

´

´

Q

f

Cl

organ

u

int

=

Cl

organ

o

+

´

Q

f

Cl

organ

u

int

clinical relevance of drug binding
Clinical relevance of drug binding
  • The importance of plasma protein binding displacement interaction has been overestimated and overstated
case for which we need to know in vivo free concentration
Case for which we need to know in vivo free concentration

For extrapolation

  • from in vitro to in vivo
    • in vitro, Kd (binding) and EC50 (functional response) are free concentrations but EC50 (for PK/PD) is total concentration
    • CMI (free) vs effective plasma concentration (Ctot)
  • between species
    • comparison of EC50 between animals requires to take into account free fraction
the classical example phenylbutazone warfarin interaction
The classical example: Phenylbutazone/warfarin interaction
  • Interaction actually exists
  • Displacement actually exists
  • but the plasma binding displacement is not the underlying mechanism of interaction
    • PBZ stereoselectivity inhibits the metabolism of s-warfarin
why plasma binding seldom has clinical relevance
Why plasma binding seldom has clinical relevance
  • Because few drugs (so-called displacer) are therapeutically used
  • Because when displacement exists, it has no consequence on the receptor exposure to the freeconcentration of the displaced drug which generally remains unaffected
is there often displacement of drug from the binding site
Is there often displacement of drug from the binding site?
  • No
  • For a substantial displacement to take place, the displacer must occupy most of the available binding site thereby lowering the binding site available to the primary drug
is there often displacement of drug from the binding site13
Is there often displacement of drug from the binding site?
  • No
  • To take place, the molar concentration of the drug in plasma must exceed the molar concentration of albumin (150 µg/mL for a a drug with a MW of 250)
    • e.g.: PBZ, phenytoin, valproic acid
  • This is not true for a1-glycoprotein acid (basic drug)
why plasma protein displacement seldom has clinical relevance
Why plasma protein displacement seldom has clinical relevance
  • Generally only the free (unbound) drug is metabolized and can access to the receptor

AND

  • the free drug concentration is controlled by the free drug clearance which is independent of the plasma binding
plasma binding proteins
Plasma binding proteins

Proteins MW Concentration

g/L µM

Albumin 67 000 35-50 500-700

-glycoprotein 42 000 0.4-1.0 9-23

acid

Lipoproteins 200 000 variable

to 2.4 106

Transcortin 53 000 0.03-0.07 0.6-1.4

slide17
Drug binding protein concentration and percentage of free drug in serum of healthy dogs and dogs with inflammation

Healthy Inflammation level of significance

Total protein (g/L) 71.6 72.3 NS

Albumin (g/L) 31.3 27.6 xxx

a-acid glycoprotein (mg/L) 374 1632 xxx

Percentage free

Lidocaine 43.5 11.7 xx

Propanolol 27.8 9.3 xx

Phenytoin 18.1 17.6 NS

Digitoxin 15.5 18.9 xx

Diazepam 1.57 2.78 x

Baggot The physiological basisof vet clin pharmacol p.103

drug plasma protein binding
Drug plasma protein binding
  • Expressed in % or by fu (free fraction)
  • >90% = highly bound
the free fraction fu
The free fraction : fu
  • fu = =

Definition:

free concentration

total concentration

Cfree

Ctot

fu and Cfree are not synonymous terms

slide22

Cbound

Bmax

KD

Cfree

The bound concentration

  • The bound concentration

Bmax/2

  • Bmax : maximal concentration of
  • binding sites
    • proportionnal to plasma protein concentration
  • KD : free drug concentration corresponding to half maximal binding
    • inversely proportional to drug affinity for the protein
c tot is a function of c free
Ctot is a function of Cfree

Ctot = Cfree + Cbind

Ctot = Cfree +

Bmax x Cfree

Kd + Cfree

Dependent variable

Parameters

Independent variable controlled by Clfree

the free fraction fu25
The free fraction fu
  • Physiological factors controlling fu
  • fu = =

Cfree

Cfree + Cbind

Cfree

Ctot

slide26

The unbound fraction : fu

  • Linear binding : Cfree << KD
slide27
Total concentration:a convenient but illicit rearrangement which can be misleading when discussing drug interaction

Cfree = fu x Ctotal

indirectly estimated

known from in vitro assay

measured by analytical technique

total concentration
Total concentration

Ctot =

  • When conceptualizing dependency and functionality, this equation should not be rearranged

Cfree

fu

!

total concentration why the free displaced drug concentration is not controlled by plasma binding
Total concentration:Why the free displaced drug concentration is not controlled by plasma binding

The fundamental relationship

Total concentration =

independent variable

free concentration

fu

(free fraction)

parameters

dependent variable

Where fu is altered, Ctot is modified, not Cfree

slide30
Total concentration:a convenient but illicit rearrangement which can be misleading when discussing drug interaction
  • What is the consequence of fu 
  • Ctot  = or Cfree  = fu  x Ctotal

Cfree

fu 

NO

YES

Displacement (fu) modifies Ctot, not Cfree

slide32

AND

Bmax

Kd

Definition

Physiological relationship

drug interaction and protein binding33
Drug interaction and protein binding
  • Ctot = Cfree +

Bmax x Cfree

Kd + Cfree

possible interaction

Interaction will modify Ctot but not Cfree

slide34
Conditions in which the plasma concentration of the 2 major plasma proteins to which drug binds are altered

Conditions Change in concentration

Albumin hepatic cirrhosis 

burns 

nephritic syndrome 

pregnancy 

a-glycoprotein myocardial infarcts 

surgery 

trauma 

rheumatoid arthritis 

Rowland p.152

competitive interaction
Competitive interaction

Ctot = Cfree +

Ctot is decreased

Bmax x Cfree

Kd (1 + A/Ki) + Cfree

Displacement

competitive interaction36
Competitive interaction
  • Case of restrictively eliminated drug

Clfree = Clint = constant Cltot = fu x Clint

perfusion rate: K0

Ctot

Cltot

Cfree

Clfree = cst

redistribution

Administration of the 2nd ligand, displacement  fu

competitive interaction for restrictively eliminated drugs

Competitive interaction for restrictively eliminated drugs

when interaction occurs, Ctot is altered not Cfree

slide39

In vitro - closed system

In vivo - open system

Drug with low extraction ratio

Css, tot

=

constant

Css, free

perfusion

rate

constant

=

=

Cl

Css, free

=

f

C

1

int

Css, tot

u

ss,

tot

Css, free

=

fu

if fu then Ctot

if fu then Cfree

Effect

1.0

1.0

Ctot

fu = 0.4

0.5

Ctot

fu = 0.2

0.5

fu = 0.2

Cfree

fu = 0.4

0.2

0.2

Cfree

Time

Time

Competitive interaction

Competitive interaction

fu vs cfree in vitro situation
fu vs Cfree: in vitro situation

4

4

2

1

fu = 0.5

Cfree = 3/V

Ctot = 6/V

2

1

5

5

3

3

6

6

fu = 0.83 

Cfree = 5/V 

Ctot = 6/V 

displacer

displacee

V= volume of the baker

fu vs cfree in vivo situation initial steady state
fu vs Cfreein vivo situation: initial steady state

Extracellular fluid

Intracellular fluid

Plasma

4

1

2

Infusion=A

A=MT-1

K12 Cfree

5

3

6

K21 Cfree

Elimination = K10 x Cfree (3) = A equated by infusion

TOTAL CONCENTRATION = 6/V

FREE CONCENTRATION = 3/V

fu vs cfree in vivo situation just after administration of displacer

Just displaced free drug

fu vs Cfree: in vivo situation:just after administration of displacer

displacer

Extracellular fluid

Intracellular fluid

Plasma

K12xCfree: increase transitively

1

4

2

Infusion=A

A=MT-1

5

3

6

K21 x Cfree

TOTAL CONCENTRATION = 6/V 

FREE CONCENTRATION = 5/V 

Increase transitorily

K10 x Cfree (5) > A

fu vs cfree in vivo situation final steady state
fu vs Cfree: in vivo situation: final steady state

displacer

Extracellular fluid

Intracellular fluid

Plasma

K12 x Cfree

1

2

Infusion=A

A=MT-1

3

6

K21 x Cfree

TOTAL CONCENTRATION = 4/V 

FREE CONCENTRATION = 3/V 

Elimination = K10 x Cfree (3) = A

the three main exceptions to the general rule for which drug interaction has no clinical meaning
The three main exceptions to the general rule for which drug interaction has no clinical meaning

1. Rapid bolus IV injection

2. Parenteral administration of displaced drug with a high extraction ratio

3. Therapeutic drug monitoring and drug displacement from the plasma binding site

case for which drug interaction at the binding site is relevant
Case for which drug interaction at the binding site is relevant

1. Rapid IV injection

  • If the displacing agent is given rapidly (IV bolus), the Cfree could increase dramatically due to rapid displacement of the displaced drug before the compensatory mechanism (redistribution) takes place
    • Sulfamide and bilirubin  kernicterus
case for which drug interaction at the plasma binding site is relevant
Case for which drug interaction at the plasma binding site is relevant

3. Therapeutic drug monitoring and drug displacement from plasma binding

  • Therapeutic drug monitoring is performed for drugs with a narrow concentration range between therapeutic and toxic effect
  • Monitoring is carried out on total plasma concentrations
case for which drug interaction at the plasma binding site is relevant47
Case for which drug interaction at the plasma binding site is relevant

3. Therapeutic drug monitoring and drug displacement from plasma binding

  • An example:
  • Phenytoin alone: Ctot = 20 µg/mL
  • Phenytoin + Valproic acid: Ctot = 15 µg/mL
  • no dosage adjustment is necessary because Ctot decreased but not Cfree due to fu increase
slide48

Algorithm for determining clinical significance of potential binding displacement interaction

Roslan 1994, B.J.Clin Pharmacol. 37, 125

Is drug of interest >90% protein bound?

no

Clinically significant interaction not likely

Yes

no

Does the drug have a narrow therapeutic index ?

no

Yes

low

Would a transient increase in free drug concentration be clinically relevant ?

What is the hepatic extraction ratio of the drug ?

High

Yes

no

Is the drug given IV?

Clinically significant interaction likely. Perform a clinical study to quantify effects

Yes

protein binding interactions
Protein Binding Interactions

“…the overall clinical importance of plasma protein binding displacement interactions continues to be overstated…”

“Despite the theoretical and experimental data to the contrary, the concept that plasma protein binding displacement is a common cause of clinically significant interactions may still be widely taught in some medical schools, often appears in textbooks and is accepted by many in the medical community and by drug regulators.”

Sansom LN & Evans AM. Drug Safety 1995;12:227-233.

Rolan PE. Br J Clin Pharmacol 1994;37:125-128.

protein binding interactions50
Protein Binding Interactions
  • Drugs for which pure plasma protein binding displacement interactions will lead to sustained changes in Cssu
    • Extensively bound to plasma proteins
    • Nonrestrictively cleared
    • Administered by non-oral route
      • alfentanil, buprenorphine, lidocaine, verapamil
  • Very few orally administered drugs exhibiting properties of extensive plasma protein binding, high hepatic first-pass extraction and narrow therapeutic index