Biology Reference
In-Depth Information
concentration range, PDE4 is inhibited
10% and it appears unlikely, therefore,
that inhibition of the enzyme's catalytic activity contributes to clinical effects. On
the other hand, an approximately 20-35% inhibition of PDE3 may be expected
between 11 and 44
m
M that in general is perceived to at least support the acute
bronchodilatory effects found with theophylline.
Theophylline is an antagonist to adenosine A1, A2A, and A2B receptors at
K
i
of
1-10
m
M (Fozard and Hannon
1999
), which is below the therapeutic range, and as
a corollary adenosine receptor antagonism is considered to contribute to efficacy
and adverse events.
As discussed above, theophylline suppresses PI3K
d
, sensitized by oxidative
stress (EC
50
of around 1
m
M and maximum inhibition of 60% at
<
10
m
M) translat-
ing into protection of HDAC2 activity over a concentration range of 1-10
m
M
theophylline (To et al.
2010
; Barnes
2009
), which is close or below the therapeutic
plasma levels for this xanthine. Clearly, such a mechanism may more likely
contribute to clinical effects of theophylline than PDE4 inhibition.
In contrast, the standard clinical dose of roflumilast at 500
m
g OD results in
plasma levels of 1-2 nM roflumilast N-oxide (unbound to proteins) maintained over
the 24 h dosing interval, which correspond to an extrapolated 50-60% inhibition of
PDE4 translating into 20-40% inhibition of cellular functions (see Hatzelmann
et al.
2010
for a recent review). Thus, for roflumilast one may assume that clinical
efficacy is fully attributed to highly potent and selective PDE4 inhibition. Clearly,
this pharmacokinetic profile with rather stable plasma levels in the once-daily
dosing regimen represents an asset of roflumilast that distinguishes this PDE4
inhibitor from earlier competitors (Bethke et al.
2007
; Hatzelmann et al.
2010
).
This is further illustrated in Fig.
5
where the pharmacokinetic profile following
repeated dosing of roflumilast at the clinical dose of 500
m
g OD was recalculated to
the extent of PDE4B1 and PDE4D3 inhibition for the (1) sum of roflumilast and its
active metabolite and for (2) roflumilast and (3) roflumilast N-oxide alone.
100
PDE4B1
PDE4D3
ROF/RNO
Fig. 5 Extrapolated extent
of PDE4B and D inhibition
following repeated dosing
of roflumilast (500
m
g OD)
based on plasma levels.
Circles
, roflumilast;
triangles
,
roflumilast N-oxide;
diamonds
, sum of roflumilast
and roflumilast N-oxide
50
RNO
Roflumilast
0
02468 0 2 4 6 8 0 2 4
time (h)
