Drug Metabolism in Drug Design and Development Basic Concepts and Practice

de Montellano and De Voss, 2005). Some of these transformations are shown
in Fig. 2.4, but the list is certainly not comprehensive. Finally, many of the
most interesting new reactions have come out of practical issues in
understanding the metabolism of new drug candidates in the pharmaceutical
industry (Evans et al., 2004; Kalgutkar et al., 2005).

2.5.2 Flavin-Containing Monooxygenase (FMO)

The cellular location (endoplasmic reticulum) reaction stoichiometry is the
same, mixed-function oxidation, as for P450,

NADPHþO 2 þRX!RXOþNADPþþH 2 O

ðX¼N;X;PÞ

HC CCHO

NCH 2 R NCH 2 R

N CHR N CHR

N CHR NH CHR

OH O

X X OX

R

R

R

O

O

Fe4+

HO

N

R

N

N

O

R

R

R

HO N

Heteroatom

oxygenation:

Heteroatom

release:

Carbon

hydroxylation:

Epoxidation and Group

migration:

• 
  


• • •


• ••


• • •• +

+

• 
  


• • +• - +

+•

• 
  

[FeO]3+ [FeOH]3+ Fe3+

[FeO]3+ [FeO]2+

[FeOH]3+

Fe3+

[FeO]3+ [FeO]2+ Fe3+

[FeO]3+

[FeO]2+

FIGURE 2.3 Some major categories of the P450 reactions (adapted with permission
from Guengerich and Macdonald, 1984).

20 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS