Biomedical Engineering Reference
In-Depth Information
O
O
Esterase
DRUG
COR
DRUG
C
OH
+
ROH
(a)
O
O
Esterase
DRUG
O
C
R
DRUG
OH
+
RC
OH
(b)
O
O
Amidase
DRUG
NH
C
R
DRUG
NH
2
RC
OH
+
(c)
O
O
P
hosphatas
e
DRUG
O
P
OH
DRUG
OH
HO
P
OH
+
OH
OH
(d)
FIGURE 9.3
Schematic examples of prodrugs designed to undergo enzymatic-mediated hydrolysis.
of phosphates designed to undergo enzyme-catalyzed oxidative conversion into active phosphates
specii cally mediated by CYP3A4 enzymes present in the liver.
A challenge in the design of prodrugs susceptible to enzymatic conversion is the limited avail-
ability of predictive
in vitro
and
in vivo
models for selection and optimization of the prodrug
candidate.
In vitro
assays in which reaction kinetics is studied in the presence of human or animal
material such as blood, serum, plasma, and intestinal or liver tissue can provide qualitative infor-
mation on drug conversion whereas to a much lesser extent they offer quantitative predictions on
the rate and extent to which biotransformation takes place
in vivo
.
In vivo
models using experimen-
tal animals such as mice, rats, dogs, or monkeys can indeed provide
in vivo
relevant information
but suffers from the only sparse knowledge available on species differences in terms of enzyme
abundance, distribution, activity, and specii city compared to the human
in vivo
situation. Thus,
there is a risk that prodrugs dependent on bioconversion mediated by enzymes may show high
interindividual variability due to variability in enzyme levels and activity between individuals.
9.3.2 P
RODRUGS
T
RANSFORMED
BY
S
PONTANEOUS
R
EACTIONS
As an alternative to the enzymatic-mediated bioconversion, prodrugs may be designed to undergo
spontaneous (or chemical) transformation dictated by the physicochemical environment such as the
pH in various parts of the human body.
Some important examples of prodrugs biotransformed by nonenzymatic-mediated reactions
are hydroxymethyl derivatives of NH-acidic drug molecules such as 5-l uorouracil, phenytoin,
N
-Mannich bases derived from drugs containing amino or amide functions (e.g., tetracycline, car-
bamazepine) and ring-opened derivatives of cyclic drugs (e.g., pilocarpine Figure 9.5). The rate of
spontaneous transformation of
N
-hydroxymethyl prodrugs of NH-acidic drugs can be predicted
from the acidity (p
K
a
) of the parent drug compound. A linear relationship between the logarithm
to the half-life (log
t
1/2
, pH 7.4, 37°C) of
N
-hydroxymethyl derivatives and the p
K
a
of the parent
NH-acidic drug has been established allowing easy evaluation to whether a
N
-hydroxymethyl deriv-
ative may consist an attractive prodrug principle for a given drug molecule:
log
t
=
0.77
´
p
K
-
8.34
1/2
a
