Effect of E-5110, a novel non-steroidal anti-inflammatory drug, on trimethadione metabolism as an indicator of hepatic drug-oxidizing capacity in beagle dog.
1. We examined the effects of N-methoxy-3-(3,5-di-tert-butyl-4- hydroxybenzylidene pyrrolidin-2-one (E-5110), a novel non-steroidal anti-inflammatory drug, on the pharmacokinetics of trimethadione (TMO) and characterized the P450 isozymes involved in the metabolism of TMO in beagle dog. 2. In the E-5110-treated dog (50 mg/kg/day for 7 days: oral) the plasma half-life (t1/2) and the area under the curve (AUC) of TMO (4 mg/kg, i.v.) in vivo were decreased, and total body clearance (CL) was increased; the apparent volume of distribution (Vd) was relatively unchanged. 3. Contents of P450 and b5, and the activity of p-nitroanisole O-demethylase and benzphetamine N-demethylase in vitro were significantly increased compared with controls by repeated E-5110 treatment in dog. 4. Contents of CYP2B and 3A were increased by E-5110 pretreatment in dog. 5. TMO N-demethylation was inhibited by the anti-CYP2B and 3A IgG fractions in liver microsomes obtained from the E-5110-treated dog. 6. Results of both the in vivo and in vitro studies of the effects of E-5110 treatment in dog on TMO indicate that these effects may be attributed to the induction of CYP2B and 3A.
Daling
Z
Z
Eisai Research Laboratories, Eisai, Co., Ltd, Ibaraki-ken, Japan.
Tanaka
E
E
Nakamura
T
T
Horie
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D004285:Dogs; D006207:Half-Life; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D014293:Trimethadione / Q000378:metabolism / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D011760:Pyrrolidinones; C054091:E 5110; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D009575:Nitroanisole O-Demethylase; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; D014293:Trimethadione