P-Glycoprotein Mediated Antiepileptic Drug Transport; a Role in Refractory Epilepsy?
Abstract number :
1.260
Submission category :
Year :
2001
Submission ID :
1669
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
G.J. Sills, PhD, University of Glasgow, United Kingdom; P. Kwan, MD, University of Glasgow, United Kingdom; E.C.M. de Lange, PhD, Leiden/Amsterdam Center for Drug Research, Leiden, Netherlands; E. Butler, University of Glasgow, United Kingdom; M.J. Brodie
RATIONALE: Recent evidence suggests that the drug-transport molecule P-glycoprotein (P-gp), encoded by the multi-drug resistance (mdr) gene, may play a causative role in refractory epilepsy by limiting brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic investigation in genetically modified mdr1a(-/-) knock-out mice, devoid of P-gp at the blood-brain barrier, to determine whether currently used AEDs are potential substrates for P-gp transport.
METHODS: 72 mdr1a(-/-) mice were randomised to receive either phenobarbital (20mg/kg), phenytoin (20mg/kg), carbamazepine (20mg/kg), sodium valproate (200mg/kg), vigabatrin (500mg/kg), lamotrigine (5mg/kg), gabapentin (50mg/kg) or topiramate (50mg/kg) by subcutaneous injection. A parallel group of 72 wild-type (genetically normal; FVB) mice served as controls. At 30, 60 and 240 minutes post-dosing, three animals from each group were sacrificed, a truncal blood sample obtained and their brains removed. Plasma and brain samples were analysed for concentrations of appropriate AED. A brain / plasma concentration ratio was established for each drug and compared (knockout vs control) by two sample t-test.
RESULTS: Brain / plasma concentration ratios for carbamazepine (30 mins), lamotrigine (240 mins), gabapentin (30 mins) and topiramate (30, 60 & 240 mins) were significantly (p[lt]0.05) higher in mdr1a(-/-) knockout mice than in FVB wild-type controls. There were no significant differences in brain / plasma concentration ratios for the other AEDs under investigation.
CONCLUSIONS: The results of this preliminary study suggest that several currently used AEDs are potential substrates for P-gp mediated transport. Of these agents, topiramate would appear to be the most likely candidate, although more exhaustive studies are required. These findings are consistent with the hypothetical involvement of mdr gene expression and P-gp mediated drug extrusion in the causation of pharmacoresistant seizures. The role of drug transporter macromolecules in refractory epilepsy merits further detailed experimental investigation.
Support: No support.