Drug Metabolism in Drug Design and Development Basic Concepts and Practice

inhibition to occur, one would have to imagine a situation in which the
inhibitor affected the catalytic properties of the enzyme but did not affect
substrate binding. This implies that the free enzyme and the enzyme–substrate
complex would have to exhibit equal binding constants for the inhibitor, which
is unlikely. Upon careful examination, most situations originally thought to
involve noncompetitive inhibition are in fact, mixed inhibition. Thus,
noncompetitive inhibition will not be discussed here.

4.7.5 Uncompetitive Inhibition

The final type of inhibition that will be discussed is that of uncompetitive
inhibition. In this case, the inhibitor decreases the apparent value ofVmaxbut
has no effect on Vmax/Km; in other words, both Vmax and Km decrease
proportionately. Uncompetitive inhibition differs from competitive inhibition
in that the inhibitor only binds to the enzyme–substrate complex (Scheme 4.4)
and not to the free enzyme.
As with the other types of inhibition, equations have been derived that
permit estimation of the inhibition constant as well as Kmand Vmaxfor
uncompetitive inhibition (Eq. 4.19).

v¼

Vmax

1 þ½KIŠi

!

½ŠS

Km

1 þ½KIŠi

!

þ½ŠS

ð 4 : 19 Þ

That both catalytic (Vmax) and specific (Km) effects are noted in
uncompetitive inhibition is noted in the following equations. BothVmaxapp and
Kappm are reduced by the same factor (Eqs. 4.20 and 4.21):

Vmaxapp¼

Vmax

1 þ½KIŠi

ð 4 : 20 Þ

Kappm ¼

Km

1 þ½KIŠi

ð 4 : 21 Þ

such that the following equality is derived from theV/Kratios (Eq. 4.22).

Vmaxapp

Kmapp

¼

Vmax

Km

ð 4 : 22 Þ

SCHEME 4.4 Uncompetitive inhibition.

ENZYME INHIBITION KINETICS 105