4-hydroxyphenytoin-glucuronide, which is readily excreted
via the kidney.PHASE I METABOLISM
The liver is the most important site of drug metabolism.
Hepatocyte endoplasmic reticulum is particularly important,
but the cytosol and mitochondria are also involved.ENDOPLASMIC RETICULUMHepatic smooth endoplasmic reticulum contains the cytochrome
P450 (CYP450) enzyme superfamily (more than 50 different
CYPs have been found in humans) that metabolize foreign
substances – ‘xenobiotics’, i.e. drugs as well as pesticides, fertil-
izers and other chemicals ingested by humans. These metabolic
reactions include oxidation, reduction and hydrolysis.OXIDATION
Microsomal oxidation causes aromatic or aliphatic hydroxyla-
tion, deamination, dealkylation or S-oxidation. These reac-
tions all involve reduced nicotinamide adenine dinucleotide
phosphate (NADP), molecular oxygen, and one or more of a
group of CYP450 haemoproteins which act as a terminal oxi-
dase in the oxidation reaction (or can involve other mixed
function oxidases, e.g. flavin-containing monooxygenases or
epoxide hydrolases). CYP450s exist in several distinct iso-
enzyme families and subfamilies with different levels of amino
acid homology. Each CYP subfamily has a different, albeit
often overlapping, pattern of substrate specificities. The major
drug metabolizing CYPs with important substrates, inhibitors
and inducers are shown in Table 5.1.
CYP450 enzymes are also involved in the oxidative
biosynthesis of mediators or other biochemically important
intermediates. For example, synthase enzymes involved in the
oxidation of arachidonic acid (Chapter 26) to prostaglandins●Introduction 24
●Phase I metabolism 24
●Phase II metabolism (transferase reactions) 25
●Enzyme induction 27●Enzyme inhibition 28
●Presystemic metabolism (‘first-pass’ effect) 28
●Metabolism of drugs by intestinal organisms 29CHAPTER 5
DRUG METABOLISM
INTRODUCTION
Drug metabolism is central to biochemical pharmacology.
Knowledge of human drug metabolism has been advanced by
the wide availability of human hepatic tissue, complemented by
analytical studies of parent drugs and metabolites in plasma and
urine.
The pharmacological activity of many drugs is reduced or
abolished by enzymatic processes, and drug metabolism is one
of the primary mechanisms by which drugs are inactivated.
Examples include oxidation of phenytoinand of ethanol.
However, not all metabolic processes result in inactivation, and
drug activity is sometimes increased by metabolism, as in acti-
vation of prodrugs (e.g. hydrolysis of enalapril, Chapter 28, to
its active metabolite enalaprilat). The formation of polar metabo-
lites from a non-polar drug permits efficient urinary excretion
(Chapter 6). However, some enzymatic conversions yield active
compounds with a longer half-life than the parent drug, causing
delayed effects of the long-lasting metabolite as it accumulates
more slowly to its steady state (e.g. diazepamhas a half-life of
20–50 hours, whereas its pharmacologically active metabolite
desmethyldiazepamhas a plasma half-life of approximately
100 hours, Chapter 18).
It is convenient to divide drug metabolism into two phases
(phases I and II: Figure 5.1), which often, but not always, occur
sequentially. Phase I reactions involve a metabolic modification
of the drug (commonly oxidation, reduction or hydrolysis).
Products of phase I reactions may be either pharmacologically
active or inactive. Phase II reactions are synthetic conjugation
reactions. Phase II metabolites have increased polarity com-
pared to the parent drugs and are more readily excreted in the
urine (or, less often, in the bile), and they are usually – but not
always – pharmacologically inactive. Molecules or groups
involved in phase II reactions include acetate, glucuronic acid,
glutamine, glycine and sulphate, which may combine with
reactive groups introduced during phase I metabolism (‘func-
tionalization’). For example,phenytoinis initially oxidized
to 4-hydroxyphenytoin which is then glucuronidated to