on the cytochrome P450 (CYP) family of enzymes, many of the same concepts
more or less apply equally to other enzymes (e.g., nonmicrosomal and Phase II
drug-metabolizing enzymes) and drug transporters.
5.2 Enzyme Inhibition
5.2.1 Types of Inhibition
The simplest way to describe CYP enzyme catalysis is Michaelis–Menten (M–M)
kinetics, where the relationship between the rate of catalysis and substrate
concentration is best characterized by a single-binding site and a hyperbolic curve.
Most often, characterization of CYP inhibition is conducted when CYP catalysis
follows M–M kinetics to avoid complications of data interpretation. Recently,
atypical kinetics have been demonstrated for CYP catalysis, where two or more
enzyme–substrate binding sites may be involved (Houston and Kenworthy, 2000;
Shou, 2002; Shou et al., 2001). Modeling of CYP inhibition using atypical kinetics
has also been described (Houston and Galetin, 2005; Zhang and Wong, 2005).
Mechanisms of CYP inhibition can be broadly divided into two categories;
reversible inhibition and mechanism-based inactivation. Depending on the
mode of interaction between CYP enzymes and inhibitors, reversible CYP
inhibition is further characterized as competitive, noncompetitive, uncompe-
titive, and mixed (Ito et al., 1998b). Evaluation of reversible inhibition of CYP
reactions is often conducted under conditions where M–M kinetics is obeyed.
Based on the scheme illustrated in Fig. 5.1, various types of reversible
inhibition are summarized in Table 5.1. Figure 5.1 depicts a simple substrate–
enzyme complex during catalysis. In the presence of a reversible inhibitor, such
a complex can be disrupted leading to enzyme inhibition.
Mechanism-based CYP inhibition or irreversible inhibition, involves
permanent inactivation of CYP enzymes during catalysis, where reactive
intermediate(s) are formed, leading to apoprotein or heme-ion center
modification. Typical characteristics of mechanism-based enzyme inhibition
include time-dependent loss of enzyme activity, a rate of inactivation generally
following saturation kinetics, enzyme activity that cannot be recovered after
FIGURE 5.1 Reversible inhibition scheme.114 METABOLISM-MEDIATED DRUG–DRUG INTERACTIONS