Effect of E-5110, a novel non-steroidal anti-flammatory drug, on trimethadione metabolism as an indicator of hepatic drug-oxidizing capacity in beagle dog

Abstract

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 (t_1/2) 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 (V_d) 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.