P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice.
Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls. AEDs were administered by subcutaneous injection and serum and brain drug concentrations determined at 30, 60, and 240min post-dosing. The brain-serum concentration ratio for topiramate was higher in mdr1a(-/-) mice than in wild-type controls at all time points investigated. No consistent effects were observed with any other AED investigated. These findings suggest that topiramate may be a substrate for P-gp-mediated transport. Further studies employing a range of model systems are required to substantiate this observation and to address the potential role of drug transporters in refractory epilepsy.
Sills
Graeme J.
GJ
Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, UK
Kwan
Patrick
P
Butler
Elaine
E
de Lange
Elizabeth C.M.
EC
van den Berg
Dirk Jan
DJ
Brodie
Martin J.
MJ