Chemistry Reference
In-Depth Information
the attachment of very hydrophilic species such as glucuronic acid or
glycine to xenobiotics and are usually considered to terminate pharmaco-
logical action. The drug conjugate is much less lipophilic and much more
water soluble and is excreted easily by the kidneys. The situation is compli-
cated, however, because drugs can be a substrate for more than one
metabolising enzyme and there is no 'pecking order' or priority for enzyme
action. This sequential conjugation can give rise to a bewildering array of
metabolites and conjugates appearing in the urine or faeces when a drug is
administered.
The major routes for drug conjugation are shown below.
Glucuronic acid conjugation
This is perhaps the most common route of Phase 2 drug metabolism
because of the high levels of glucuronic acid in the liver and the relatively
large number of functional groups that can act as a substrate for conjugate
formation (alcohols, phenols, carboxylic acids, amines). The xenobiotic (or
its Phase 1 metabolite) reacts with the activated form of glucuronic acid
(uridine diphosphate glucuronic acid, or UDPGA) to give a derivative called
a
glucuronide
as shown in Figure 5.1.
OH
H
COO
-
COO
-
+
O
O
O
N
OH
OH
O
O-UDP
HO
HO
N
H
3
C
CH
3
OH
H
OH
O
Paracetamol
H
3
C
COOH
CH
3
COO
-
COO
-
O
+
O
O
O
CH
3
OH
OH
O-UDP
HO
HO
H
3
C
OH
OH
H
3
C
CH
3
Ibuprofen
Figure 5.1
Formation of glucuronides.
