Biology Reference
In-Depth Information
Ibudilast is excreted primarily (60%) in urine with less than 0.01% recovered as
unchanged drug (Rolan et al.
2008
).
Human pharmacokinetics of ibudilast has been investigated in Asian and Cau-
casian healthy adults (Table
1
) with single and multiple oral doses up to 30 mg BID
(Uchida et al.
1985
; Maeda et al.
1989
; Rolan et al.
2008
). After multiple oral doses,
steady state of both ibudilast and the 6,7 dihydrodiol metabolite was reached after
2-3 days (BID regimen) (Rolan et al.
2008
).
The
C
max
after oral administration of ibudilast appeared to be slightly higher
after the morning dose than after the evening dose (Rolan et al.
2008
).
In contrast to the increased clearance observed in the rat with multiple oral doses
of ibudilast, human pharmacokinetics seems to be invariant and non-inducible
with repeated doses and gives no evidence of auto-induction or time-dependent
pharmacokinetics (Rolan et al.
2008
).
4.3 Tetomilast
Tetomilast was given up to 50 mg p.o., once daily. Following a single, oral dose of
50 mg to COPD patients
C
max
was 5.7 ng ml
1
(corresponding to 16 nM), the time
to
C
max
(
t
max
) was 2.75 h, and the terminal half-life around 24 h (
t
m1/2
) allowing
once-daily administration (Mallikaarjun et al.
2006
). Tetomilast showed
linear pharmacokinetics over a range of 25-100 mg p.o., single dose. Repeated
administration resulted in a maximum twofold increase in exposure. Trough plasma
concentrations were about 30-50% of the maximum. Absolute bioavailability
following oral dosing was nearly 100% and absorption remained unaffected by
food. The volume of distribution with about 180 ml kg
1
indicates rather low
distribution to tissues. Plasma protein binding was high with
99.5%. Following
a single oral dose of radiolabeled tetomilast more than 90% of plasma radioactivity
was attributed to the parent compound. Tetomilast may be metabolized by CYP1A1
and 1A2; however, the metabolite appears to be of minor importance.
>
4.4 Cilomilast
Cilomilast is rapidly and almost completely absorbed after oral administration
(96%) (Zussman et al.
2001b
). Maximum plasma concentration (
C
max
) is reached
within 3 h following oral administration (Zussman et al.
2001b
).
Cilomilast is highly bound to plasma albumin (99%). Distribution of cilomilast
into tissues is limited (volume of distribution 12 l) (Martina et al.
2006
).
The drug is extensively metabolized by CYP 2C8 (Murdoch et al.
2004
).
Decyclopentylation, hydroxylation of the cyclopentyl ring, and glucuronidation
are the main routes of metabolism of cilomilast (Zussman et al.
2000
; Giembycz
