Another issue is that the use of the terms Phase I, Phase II, and Phase III is
discouraged, for a number of reasons (Josephy et al., 2005). First, this older
terminology implies a temporal relationship, which is definitely not the case.
Hydrolytic reactions have often been grouped with oxidation/reduction in
Phase I but have more chemistry in common with conjugation (Phase II).
Grouping reactions in these ‘‘phase’’ groups has no real usefulness, is
confusing, and has been eliminated in the author’s teaching and writing in
this area.
The concept has often been taught that the drug metabolism process is one
of making compounds more polar to facilitate excretion. This view has some
general validity but many exceptions exist.
2.3 GENERAL FEATURES OF THE ENZYMES
As already mentioned, these enzymes are usually found in multigene families
that can be complex (e.g., cytochrome P450 (P450)). The selectivity of the
individual substrates and reactions is influenced by the nature of the protein
(and ultimately, its amino acid sequence). This selectivity is a very significant
issue in drug development, although it will be mentioned only in some of the
examples used here. In some cases, the selectivity may be quite strict among the
individual forms of an enzyme, for example, only P450 2D6 catalyzes
debrisoquine 4-hydroxylation (Distlerath et al., 1985; Guengerich, 2005).
However, in other cases, several enzymes within a group or even enzymes from
different groups can catalyze the same reaction, even using different chemistry.
For instance, several P450s and flavin-containing monooxygenase (FMO) can
form certainN-oxides (Seto and Guengerich, 1993).
An extension of this issue is that all of these enzymes (or actually the
genes) show genetic polymorphism, which can influence the levels of
expression, enzyme stability, and catalytic properties. In one sense, each
allelic variant is a distinct enzyme. The majority of polymorphisms in the
coding sequences do not affect the catalytic properties of enzymes, and one
should remember that in a heterozygote the second copy should be rather
normal. However, in cases in which the therapeutic index is narrow, a
significant alteration of the catalytic activity can have a significant role, as
exemplified by the R144C and I359Lpolymorphisms with P450 2C9 and
warfarin (Daly et al., 2002).
Many of the enzymes discussed here are inducible, and another chapter will
deal with the issues. Induction can be the result of the drug under consideration
for metabolism, another drug, or a separate exposure in the diet or smoking.
Most of the enzymes discussed here can also be inhibited. One of the
considerations with new drugs is that they may inhibit the metabolism of other
drugs and lead to undesirable (and unexpected) drug interactions. A special
problem, which is not unusual, is that some inhibitors are mechanism based
and irreversible, particularly with the P450s.
16 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS