Auto-induction of E5110 metabolism, a novel non-steroidal anti-inflammatory drug, during toxicokinetic studies in beagle dogs.
Following single-dose intravenous and oral studies to determine the absolute bioavailability of E5110 in beagle dogs, repeated dose pharmacokinetic studies were conducted as toxicokinetics in a subacute toxicity test. E5110 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 E5110 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 E5110, the plasma levels of E5110 on day 15 and day 91 were markedly lower than those on the first day. On day 91, the AUCs for E5110 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 E5110 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 E5110 was increased, and Western blot analysis indicated an induction of CYP2B and 3A; therefore CYP3A may contribute to a main metabolic pathway of E5110. These results suggested that the decrease in plasma concentrations of E5110 that were observed during repeated administration represents a typical case of auto-induction of the phenobarbital type.
Nakata
H
H
EMP R&D Section, Eisai Co., Ltd., Tokyo, Japan.
Sagami
F
F
Horie
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011760:Pyrrolidinones; C054091:E 5110; D003577:Cytochrome P-450 Enzyme System