Chemistry Reference
In-Depth Information
Table 12.2 Pharmacokinetic parameters of PF-184298 in plasma following
oral administration to rats and dogs.
Rat (n
¼
2)
a
Dog (n
¼
2)
a
Dose (mg kg
1
)
1.7
0.05
C
max
(ngmL
1
)
81 (74-88)
2.2 (1.2-3.2)
T
max
(h)
0.4 (0.25-0.5)
0.6 (0.5-0.75)
t
1/2
(h)
1.1 (1.0-1.3)
2.6 (1.8-3.3)
AUC
0
N
(ng hmL
1
)
394 (328-459)
6.8 (3.6-10)
F (%)
50
28 (24-30)
a
Data presented as arithmetic mean; figures in parentheses represent range.
Cl
O
Cl
O
+16
Cl
Cl
N
N
+16
H
H
Metabolite A
Metabolite B
Cl
O
Cl
N
H
PF-184298
Cl
O
Cl
O
Cl
Cl
N
N
+46
+14
H
H
Metabolite C
Metabolite D
Figure 12.13
Metabolism of PF-184298 in preclinical studies.
excretion of a large number of metabolites, the majority of which were excreted
in urine (metabolite B) and were also formed in dog hepatocytes, providing
further evidence that hepatic metabolism plays an important role in the
clearance of PF-184298. There was no evidence for significant renal or hepa-
tobiliary elimination in the dog or rat; in total, unchanged PF-184298 in dog
accounted for no more than 15% of total radioactivity excreted (with only 2%
of the dose eliminated unchanged in urine), and elimination in rat bile
accounted for
o
1% of the administered dose. Metabolism studies in human
in vitro systems were hindered by the slow turnover of PF-184298
(9 mLmin
1
mg
1
in human liver microsomes). Furthermore, this prevented a
quantitative assessment of
the contribution of CYP-mediated oxidative
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