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-diphenylethyl) acetamide hydrochloride] is being evaluated as a novel neuroprotective treatment for epilepsy and stroke. Preliminary safety evaluation studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic enzyme 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.day-1 for 28 days) or an equivalent volume of vehicle (controls). The interpretation of the findings was aided by comparison with the effects 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 +/- 0.40 nmol.mg-1 vs. 1.31 +/- 0.19 nmol.mg-1 in controls) or ethoxyresorufin O-deethylase activity (a CYP1A induction probe) were observed after remacemide treatment. The pattern of induction produced by remacemide was very similar to that observed with phenobarbitone. The nonspecific CYP-dependent reaction ethoxycoumarin O-deethylation was induced approximately 2-fold. The specific CYP2B markers pentoxyresorufin O-depentylase and 16 beta-hydroxytestosterone production were both increased markedly by FPL 12924AA (approximately 100- and 20-fold, respectively). 2 beta- and 6 beta-Hydroxytestosterone production were also elevated, indicating the induction of CYP3A1/2. Similar effects on isoform-selective P450-dependent activities were observed in male and female mice treated with remacemide as part of a dose-ranging study.(ABSTRACT TRUNCATED AT 250 WORDS)
Riley
R J
RJ
Department of Drug Metabolism and Pharmacokinetics, Huntingdon Research Centre Ltd., UK.
Lambert
C
C
Cooper
A E
AE
Richmond
H
H
Hall
M
M
Jordan
M C
MC
Logan
C J
CJ
Clark
B
B
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000096:biosynthesis; D010170:Palmitoyl-CoA Hydrolase / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism
D000081:Acetamides; D000927:Anticonvulsants; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D014453:Glucuronosyltransferase; D010170:Palmitoyl-CoA Hydrolase; C067553:remacemide