Influence of cytochrome P450 induction on the pharmacokinetics and pharmacodynamics of remacemide hydrochloride

Sills, G. J., Santangeli, S., Forrest, G. and Brodie, M. J. (2002) Influence of cytochrome P450 induction on the pharmacokinetics and pharmacodynamics of remacemide hydrochloride. Epilepsy Research, 49(3), pp. 247-254. (doi: 10.1016/S0920-1211(02)00049-9) (PMID:12076846)

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Abstract

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 (CYP450) 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 CYP450 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 CYP450 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Brodie, Professor Martin and Sills, Dr Graeme
Authors: Sills, G. J., Santangeli, S., Forrest, G., and Brodie, M. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Epilepsy Research
Publisher:Elsevier
ISSN:0920-1211
ISSN (Online):1872-6844

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