Biology Reference
In-Depth Information
Table 2 Comparison of enzymatic and cellular findings with human
C
max
for oral PDE4 inhibitors
Oral PDE4 inhibitor
PMN/ROS (plasma) Ratio
#
PDE4B
PDE4D
Selectivity
LPS/TNF wb
C
max
(human) Clinical dose
IC
50
(nM)
IC
50
(nM)
Fold
IC
30
(nM)
IC
35
(nM)
fold
nM
0.75 mg TID, p.o., d28
a
Rolipram
230
120
1,000
500
90
0.2
40
3,300
b
3,700
b
30 mg BID, p.o., d16
c
Ibudilast
0.7 (PDE10) ND
ND
ND
260
50 mg p.o., single dose
d
Tetomilast
380
ND
8 (PDE3)
30,200
9,120
0.3
16
15 mg BID, p.o., d9
e
Cilomilast
140
20
150
5,000
1,000
0.2
7,800
Oglemilast
0.3
ND
>
1,000
90
1,820
20
Unknown
800
m
gOD
0.5 mg OD, p.o., d7
f
Roflumilast
0.7
0.4
>
1,000
50
90
1.8
15
Roflumilast N-oxide
1.5
0.8
>
1,000
50
110
2.2
52
>
300 316 912 2.8 450 20 mg OD, p.o., d29
h
Data for inhibition of PDE4B1 and PDE4D3 catalytic activity, PDE isoenzyme selectivity, LPS-induced TNF-
a
release in human whole blood (LPS/TNF wb),
and fMLP-induced superoxide release from human PMN in the presence of 80% human autologous plasma (PMN/ROS (Plasma)) were generated by one of the
authors (A.H.) according to the methods described in Hatzelmann and Schudt (
2001
), with the exception of Ibudilast, taken from Gibson et al. (
2006
) and
apremilast (PDE4B2 and PDE4D3, inhibition of catalytic activity) taken from Schafer et al. (
2010
). For the LPS/TNF wb and PMN/ROS (plasma) assay, IC30
and IC35 refer to half-maximum inhibition given that the efficacy achieved with a PDE4 inhibitor was 60 and 70% inhibition, respectively. Plasma total
C
max
values at the indicated clinical doses are obtained from the references listed below. ND is not done.
#
Ratio is the IC
35
(PMN/ROS, plasma) divided by IC
30
(LPS/TNF wb)
a
Laux et al. (
1988
)
b
Gibson et al. (
2006
)
c
Rolan et al. (
2008
)
d
Mallikaarjun et al. (
2006
)
e
Zussman et al. (
2001a
)
f
Bethke et al. (
2007
)
g
Schafer et al. (
2010
)
h
Gottlieb et al. (
2008
)
33/49
g
ND/30
g
Apremilast
