Following single-dose intravenous and oral studies to determine the absolute bioavailability of
E
5110 in beagle dogs, repeated dose pharmacokinetic studies were conducted as toxicokinetics in a subacute toxicity test.
E
5110 was administered orally once a day for
91
days at doses of 0, 1, 10, 50 and 250 mg / kg / day to dogs.On the first day during repeated administration, the Cmax and AUC values of
E
5110 in females were lower than those for males, and it seems that this may be due to a sex-related difference in the activity of cytochrome P450(CYP)3A. During repeated administration of
E
5110, the plasma levels of
E
5110 on day 15 and day
91
were markedly lower than those on the first day. On day
91
, the AUCs for
E
5110 were 55.
9
%, 38.
8
%, 10.
9
% and 7.
8
% in males, and 76.2%,
80
.3%, 10.
5
% and 11.
9
% in females on the first day, for doses of 1, 10, 50 and 250 mg / kg / day, respectively.Liver microsomes prepared after the last dose of
E
5110 showed increased activities of benzphetamine N-demethylase, p-nitroanisole O-demethylase, and aminopyrine N-demethylase, at doses of 1 mg / kg / day or more. A dose-dependent increase in P450 content was also observed. Furthermore, the capacity for
5
-hydroxylate
E
5110 was increased, and Western blot analysis indicated an induction of CYP2
B
and 3A;therefore CYP3A may contribute to a main metabolic pathway of
E
5110.These results suggested that the decrease in plasma concentrations of
E
5110 that were observed during repeated administration represents a typical case of auto-induction of the phenobarbital type.
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