Chemistry Reference
In-Depth Information
Figure 7.1
Time course of CNS effect following oral dosing.
(8-43 L kg
1
), resulting in long elimination half-lives (16 to 430 h) and slow
time to maximal compound concentration (T
max
) (typically 4-8 h after oral
dosing).
11
Oral CNS microdialysis studies in rodents conducted at Pfizer
demonstrated that systemic T
max
broadly correlated with time to peak central
5-HT levels, as shown for fluoxetine in Figure 7.1,
12
suggesting that reducing
T
max
could lead to more rapid elevation in central 5-HT, consistent with our
goal of achieving rapid onset of effect.
The delayed T
max
of lipophilic amines such as the SSRIs has been explained
as being due to the extensive distribution of high V
D
compounds into the liver
after they are absorbed,
13
which results in a slow hepatic transit time. Targeting
compounds with lower V
D
should therefore lead to compounds with more rapid
T
max
. As the half-life of a compound in vivo is described by eqn (7.1), where Cl
P
is plasma clearance, reducing the V
D
would also help achieve a shorter t
1/2
:
14
t
1=2
¼
0:693
V
D
Cl
P
ð
7:1
Þ
Another way of decreasing the half-life is to increase clearance, but there is a
limit to how high the clearance can be without adversely affecting bioavailability
(F), as shown by eqn (7.2) (Cl
H
is hepatic clearance and Q
h
is hepatic blood flow):
F
¼
1
Cl
H
Q
h
ð
7:2
Þ
Using these equations helped us set a realistic target for both volume of distri-
bution and clearance. Aiming for a minimum oral bioavailability of 50% and
assuming a compound is fully absorbed and mainly cleared by the liver
(Cl
P
¼
Cl
H
) provides a maximum acceptable clearance number of 10mL
min
1
kg
1
(taking a liver blood flow value of 20mLmin
1
kg
1
for man). Using
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