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 > School 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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