INDUCTION OF RODENT HEPATIC DRUG-METABOLIZING ENZYME-ACTIVITIES BY THE NOVEL ANTICONVULSANT REMACEMIDE HYDROCHLORIDE

Remacemide hydrochloride [FPL 12924AA; 2-amino-N-(1-methyl-1,2-dipheny lethyl) acetamide hydrochloride] is being evaluated as a novel neuropr otective treatment for epilepsy and stroke, Preliminary safety evaluat ion studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic e nzyme induction, To examine this further, the levels and activities of the major drug metabolizing cytochrome P450 (CYP) subfamilies (CPY1, CYP2, and CYP3) were monitored in microsomal samples from male Sprague -Dawley rats dosed by gavage with FPL 12924AA (250 mg base . kg(-1). d ay(-1) for 28 days) or an equivalent volume of vehicle (controls), The interpretation of the findings was aided by comparison with the effec ts of phenobarbitone (75 mg . kg(-1). day(-1) ip for 4 days) and beta- naphthoflavone (a single intraperitoneal dose at 80 mg . kg(-1). day(- 1)). No significant changes in total hepatic P450 levels (1.44 +/- 0.4 0 nmol . mg(-1) vs. 1.31 +/- 0.19 nmol . mg(-1) in controls) or ethoxy resorufin O-deethylase activity (a CYP1A induction probe) were observe d after remacemide treatment, The pattern of induction produced by rem acemide was very similar to that observed with phenobarbitone. The non specific CYP-dependent reaction ethoxycoumarin O-deethylation was indu ced approximate to 2-fold. The specific CYP2B markers pentoxyresorufin O-depentylase and 16 beta-hydroxytestosterone production were both in creased markedly by FPL 12924AA ( approximate to 100- and 20-fold, res pectively), 2 beta- and 6 beta-Hydroxytestosterone production were als o elevated, indicating the induction of CYP3A1/2. Similar effects on i soform-selective P450-dependent activities were observed in male and f emale mice treated with remacemide as part of a dose-ranging study. Im munoblot analysis demonstrated that remacemide treatment increased the levels of rat CYP2B, CYP2C, and CYP3A products. Although these data d emonstrate that remacemide is a phenobarbitone-type inducer in rodents , clinically significant hepatic enzyme induction is not anticipated a t therapeutic doses (<15 mg . kg(-1). day(-1)). This information shoul d prove valuable in the design and interpretation of ongoing preclinic al and clinical studies with remacemide.