P-glycoprotein-mediated efflux of antiepileptic drugs: Preliminary studies in mdr1a knockout mice

Graeme J. Sills, Patrick Kwan, Elaine Butler, Elizabeth C.M. de Lange, Dirk Jan van der Berg, Martin J. Brodie

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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 240 min 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.

Original languageEnglish
Pages (from-to)427-432
Number of pages6
JournalEpilepsy and Behavior
Volume3
Issue number5
DOIs
Publication statusPublished - 1 Oct 2002
Externally publishedYes

Keywords

  • Antiepileptic drugs
  • Multidrug resistance
  • P-glycoprotein
  • Pharmacokinetics
  • Refractory epilepsy

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