Drug Metabolism in Drug Design and Development Basic Concepts and Practice

TABLE 5.1 Types of inhibition (when catalysis conforms to Michaelis–Menten kinetics)

a.

Reversible

Mode of inhibitor

binding

Kinetic equation

IC

50

versus

K

i

Competitive

Unbound enzyme

V

¼

V

max

=ð

1

þ

K

m

=S

=ð

1

þ

I=

K

ÞÞi

IC

50

¼

K

ði

1

þ

S=

K

m

Þ

Uncompetitive

Substrate-bound enzyme

V

=

V

max

/(1 + I/

K

+i

K

m

/S

)IC

50

=

K

(^) i
(1 +
S/
K
m
)
Noncompetitive
Unbound and bound enzyme
at different site(s) of substrate–enzyme binding site
V
¼
V
max
=ð
1
þ
K
=s
SÞ
=ð
1
þ
I=
K
Þi
IC
50
¼
K
i
Mixed
Unbound and bound enzyme
at the same and different site(s)of substrate–enzyme binding site
V
¼
V
max
=ðð
1
þ
I=
K
0 Þi
þð
1
þ
K
=s
SÞð
1
þ
I=
K
ÞÞi
IC
50
¼
K
ði
1
þ
S=
K
m
Þ=
ð^1
þ
K
=i
K
0 Þði
S=
K
m
ÞÞ
Metabolism-based
IrreversibleMI-complex
kabs
¼
kinact
I=
ðK
þi
IÞ
Time-dependent formation of
potent reversible inhibitor
Abbreviations
:V
, velocity at a given substrate concentration;
Vmax
, maximum velocity;
K
, the binding affinity between substrate and enzyme;m
Ks
, dissociation
constant of substrate–enzyme complex;
K
, dissociation constant of inhibitor–enzyme complex;i
Kobs
, rate of inactivation at a given inhibitor concentration;
kinact
, maximal rate of inactivation;
K
, half maximal rate of inactivation (exact physical meaning is not defined); MI, metabolite–intermediate;I
Ki
0 , dissociation
constant of inhibitor–enzyme complex in the presence of substrate;
S, substrate concentration; IC
50
, concentration of inhibitor that gives rise to a 50% decrease
in activity.aSegel (1993); Silverman (1988); Zhang and Wong, 2005.
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