Biology Reference
In-Depth Information
protein binding). These are inhibition of LPS-induced TNF-
a
release from human
whole blood and inhibition of superoxide release from fMLP-stimulated human
polymorphonuclear cells (PMN) in the presence of 80% human autologous plasma
(Hatzelmann and Schudt
2001
). Comparing the potency of the different PDE4
inhibitors in the two assays reveals a group of compounds (Rolipram, Tetomilast,
and Cilomilast) that were more potent in suppressing neutrophil superoxide release
compared to LPS-induced TNF-
a
release from human whole blood. For another
group of compounds, encompassing roflumilast (launched in EU for severe COPD)
and apremilast (with promising results from clinical studies in psoriasis) but also
oglemilast, their potency to reduce neutrophil superoxide formation (80% plasma)
was inferior to that involved with diminishing LPS-induced TNF-
a
release in the
whole-blood assay. For rolipram following repeated dosing of 750
m
g three times
daily, the
C
max
of about 40 nM was closer to the half-maximum inhibition of fMLP-
stimulated superoxide release from PMN (90 nM) than to half-maximum inhibition
of LPS-induced TNF-
a
release in human whole blood (500 nM). On the other hand,
for roflumilast N-oxide the
C
max
(52 nM) after repeated dosing was in the range of
half-maximum TNF-
a
reduction in the whole-blood assay (50 nM) although below
the half-maximum inhibition of superoxide generation from PMN (110 nM). In
this respect, apremilast showed a rather comparable behavior to roflumilast. For
cilomilast, however, while as for roflumilast N-oxide and apremilast, plasma
C
max
after repeated dosing was well in the range of the compound's potencies in the two
in vitro assays, at the peak plasma levels of 7.8
m
M cilomilast neutrophil superoxide
release (80% plasma) may have been more completely attenuated than LPS-
induced TNF-
a
formation in the whole-blood assay. One may reiterate here the
earlier observation that inhibition of some neutrophil functions was considered to
correlate to emesis (Barnette et al.
1998
).
Curiously, for tetomilast peak plasma concentrations reached after a single oral
dose of 50 mg as given in a communication by Otsuka (Mallikaarjun et al.
2006
) was
much less than it would have been required for inhibition of the above-mentioned
two functional readouts (50 mg once daily was given in the clinical studies). While
repeated dosing may bear the potential of somewhat increasing
C
max
and total
exposure, such an effect may not be expected to fully account for the difference.
Also for ibudilast, peak plasma levels following repeated oral dosing of 30 mg
BID were below IC
50
values for PDE4 inhibition, in particular considering a plasma
protein binding of
95% (Sanftner et al.
2009
), resulting in peak plasma levels
unbound to protein of
13 nM (according to Kyorin's packing insert ibudilast is
recommended three times daily at 10 mg per dose).
As an unselective PDE inhibitor with some preference to inhibit PDE3 (IC
50
of
110
m
M) over PDE4B (IC
50
of 660
m
M), theophylline is not listed in the table.
However, this xanthine represents an example for a compound that was long
assumed to exert clinical effects also by PDE4 inhibition. But finally it does not
as reflected by some simple extrapolations from plasma levels. The recommended
plasma concentrations for theophylline are well-known as between 5 and 20 mg l
1
corresponding to 28-112
m
M total. With a plasma protein binding of about 60%,
the concentrations unbound to proteins are between 11 and 44
m
M. Over this
