title: P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice.
abstract: 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.
authors.affiliation: Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, UK
authors.forename: Graeme J.
authors.initials: GJ
authors.lastname: Sills
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
authors.forename: Elaine
authors.initials: E
authors.lastname: Butler
authors.forename: Elizabeth C.M.
authors.initials: EC
authors.lastname: de Lange
authors.forename: Dirk Jan
authors.initials: DJ
authors.lastname: van den Berg
authors.forename: Martin J.
authors.initials: MJ
authors.lastname: Brodie