binding- 4
Relevance of plasma and tissue
protein binding
binding- 5
Influence of drug binding on
pharmacokinetic parameters
Distribution
fu
VD VPlasma VTissue
f uT
Elimination
Q organ f u Cl int
Cl organ
Q organ f u Cl int
binding- 6
Clinical relevance of drug binding
binding- 7
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
binding- 8
The problem of drug interaction
and displacement has been
overestimated
binding- 9
The classical example:
Phenylbutazone/warfarin interaction
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
binding- 12
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 g/mL for a a
drug with a MW of 250)
e.g.: PBZ, phenytoin, valproic acid
This is not true for 1-glycoprotein acid
(basic drug)
binding- 13
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
binding- 14
Plasma drug protein binding
Physiological aspects
binding- 15
Plasma binding proteins
Proteins MW Concentration
g/L M
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
binding- 16
Drug binding protein concentration and
percentage of free drug in serum of healthy
dogs and dogs with inflammation
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
binding- 28
Drug plasma protein binding
binding- 29
The free fraction : fu
Definition:
binding- 32
The bound concentration
Cbound
The bound concentration
Bmax
B max Cfree
Cbound
K D Cfree Bmax/2
Bmax x Cfree
Ctot = Cfree +
Kd + Cfree
binding- 34
Relationship between fu, the Free
and the bound concentrations
binding- 35
The free fraction fu
Physiological factors controlling fu
fu =
Cfree
= Cfree
ctot
cfre
Cfree
fu
B max Cfree
Cfree
Kd Cfree
binding- 36
The unbound fraction : fu
Cfree K D Cfree
fu fu
Cfree Cbound B max K D Cfree
KD
fu
B max K D
binding- 38
Total concentration:
a convenient but illicit rearrangement
which can be misleading when
discussing drug interaction
Cfree = fu x Ctotal
binding- 39
Total concentration
Ctot = Cfree
fu
binding- 40
Total concentration:
Why the free displaced drug concentration
is not controlled by plasma binding
free concentration
Total concentration =
fu
(free fraction)
Cfree
Ctot = or Cfree = fu x Ctotal
fu
YES NO
binding- 46
Cfree Cfree
fu
Ctot
AND Ctot
Ctot
fu
fu
Cfree
Bmax
Kd
Definition
Physiological relationship
binding- 48
Drug interaction and protein binding
Bmax x Cfree
Ctot = Cfree + possible interaction
Kd + Cfree
binding- 49
Conditions in which the plasma
concentration of the 2 major plasma
proteins to which drug binds are altered
Bmax x Cfree
Ctot = Cfree +
Kd (1 + A/Ki) + Cfree
Displacement
Ctot is decreased
binding- 55
Competitive interaction
Case of restrictively eliminated drug
Clfree = Clint = constant Cltot = fu x Clint
perfusion rate: K0
Ctot
Cltot
Cfree
redistribution Clfree = cst
binding- 62
in vitro vs. in vivo situation
binding- 67
In vitro - closed system In vivo - open system
Drug with low extraction ratio
fu = 0.4
0.5 fu = 0.2 0.5 fu = 0.2 Ctot
Cfree
fu = 0.4
0.2 0.2 Cfree
Time Time
5 5
3 3
6 6
binding- 69
fu vs Cfree
in vivo situation: initial steady state
Plasma Extracellular fluid Intracellular fluid
4 1
2
Infusion=A 5
K12 Cfree
A=MT-1 6
3
K21 Cfree
4 1 K12xCfree: increase
2 transitively
Infusion=A
5
A=MT-1 6
3
K21 x Cfree
Just
displaced TOTAL CONCENTRATION = 6/V
Increase transitorily FREE CONCENTRATION = 5/V
free drug
K10 x Cfree (5) > A
binding- 71
fu vs Cfree:
in vivo situation: final steady state
displacer
Plasma Extracellular fluid Intracellular fluid
1 K12 x Cfree
2
Infusion=A
A=MT-1 6
3
K21 x Cfree
binding- 74
Case for which drug interaction at
the plasma binding site is relevant
binding- 76
Case for which drug interaction at
the plasma binding site is relevant
binding- 77
Algorithm
Algorithm for
for determining
determining clinical
clinical significance
significance
of
of potential
potential binding
binding displacement
displacement interaction
interaction
Roslan 1994, B.J.Clin Pharmacol. 37, 125
Is drug of interest >90%
protein bound? no
Yes Clinically significant
no interaction not likely
Does the drug have a
narrow therapeutic index ? no
Yes low Would a transient increase
What is the hepatic extraction in free drug concentration
ratio of the drug ? be clinically relevant ?
High Yes
Is the drug given IV? no
binding- 80