Biotransformations of Drugs and Chemicals
59
dehydrogenase by drugs such as disulf-
ram [Et
2
NC(S)SSC(S)NEt
2
]orbyme
tabo
-
lites oF other drugs that also give stable
adducts with the catalytic thiol group
causes hypersensitivity to the noxious
eFFectsoFethanol
.ThispropertyoFdisulf-
ram has been exploited in the treatment oF
chronic alcoholism.
3.4
Esterases and Amidases
The hydrolysis oF esters and amides, a very
general metabolic pathway, is catalyzed by
a diverse group oF carboxylesterases. These
enzymes diFFer in their mechanisms and
substrate specifcities but commonly cat-
alyze ester and amide, as well as thioester,
hydrolysis. Many oF the carboxylesterases
are serine hydrolases in which an active
site serine catalyzes the hydrolytic reac-
tion, but enzymes oF other types are also
involved. Large concentrations oF these en-
zymes are Found in the liver and kidney,
but they can be Found in most tissues. As a
rule, ester hydrolysis occurs more rapidly
than amide hydrolysis, in accord with the
relative susceptibilities oF the two Function-
alities toward chemical hydrolysis.
The carboxylesterases hydrolyze esters
to the carboxylic acid and alcohol, and
amides to the corresponding carboxylic
acid and amine.
RCO
2
R
0
−−−→
RCO
2
H
+
R
0
OH
RCONR
0
R
00
−−−→
RCO
2
H
+
R
0
NHR
00
Ester and amide hydrolysis greatly in-
creases the polarity oF the substrate, as
it replaces the neutral ester or amide
Function with a highly ionized (at pH 7)
carboxylic acid group. The amine group re-
leased by amide hydrolysis is also likely to
be protonated at physiological pH, and the
alcohol, albeit not ionized, is likely to be
more polar due to the presence oF the
hydrogen-bonding hydroxyl group. ±ur-
thermore, the Functionalities unmasked by
ester or amide hydrolysis are susceptible to
glucuronidation, sulFation, and/or amino
acid conjugation (See Sect. 4).
Esterifcation is oFten used to convert
drugs to prodrugs From which the parent
drugs are released metabolically at rates,
or in tissue locations, that improve the
pharmacokinetic properties and therapeu-
tic activities oF the drugs. ±or example,
fluphenazine is a short-lived antipsychotic
agent that must be administered several
times a day to be eFFective. Esterifcation
with a short-chain Fatty acid, however,
yields a derivative that can be adminis-
tered in a single, relatively large dose that is
deposited in adipose tissue. Hydrolytic re-
lease oF therapeutic doses oF fluphenazine
From the ester occurs over a period oF two
to Four weeks (±ig. 5).
3.5
Epoxide Hydrolases
Th
eh
y
d
r
o
l
y
s
i
so
Fe
p
o
x
i
d
e
si
sc
a
t
a
l
y
z
e
d
by epoxide hydrolases located in both the
N
S
CF
3
N
N
O
O
(CH
2
)
4
CH
3
N
S
CF
3
N
N
OH
Fluphenazine
Fig. 5
Fatty acid ester derivatives of fluphenazine are lipophilic prodrugs from which fluphenazine,
the active principle, is released by enzymatic hydrolysis.
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