Influence of cytochrome P450 induction on the pharmacokinetics and pharmacodynamics of remacemide hydrochloride.
Remacemide hydrochloride (RMD) is a putative anticonvulsant agent with an active metabolite, desglycinyl-remacemide (DGR) and a broad spectrum of activity in experimental seizure models. In clinical trials, however, the efficacy of RMD is questionable. In the case of add-on studies, the inconclusive findings may be related to pharmacokinetic interactions between RMD and established antiepileptic drugs. We have investigated the influence of cytochrome P450 (CYP(450)) induction following repeated treatment with phenobarbital (PB) on the pharmacokinetics and pharmacodynamics of RMD in mice. Pre-treatment with PB (80 mg/kg; once daily for 4 days) significantly increased CYP(450) content and activity in mouse liver. This was associated with a consistent reduction in the brain concentrations of both RMD and DGR and attenuation of the anticonvulsant effects of RMD in the maximal electroshock model. Pharmacokinetic analysis suggested that DGR was proportionately more susceptible to CYP(450) induction than the parent compound. As the principal active moiety, the selectively enhanced metabolism of DGR under induced conditions may underlie the debatable findings of add-on trials with RMD in refractory epilepsy. However, this hypothesis does not explain the similarly questionable efficacy of RMD monotherapy in newly diagnosed epilepsy, an observation that may have wider pharmacological implications.
Sills
Graeme J
GJ
Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G116NT, UK. g.j.sills@clinmed.gla.ac.uk
Santangeli
Sarah
S
Forrest
Gerard
G
Brodie
Martin J
MJ
D000081:Acetamides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000379:methods; D004790:Enzyme Induction / Q000502:physiology; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR
D000081:Acetamides; D003577:Cytochrome P-450 Enzyme System; C067553:remacemide