The transport of antiepileptic drugs by P-glycoprotein ☆ Chunbo Zhang a , Patrick Kwan b, c, d , Zhong Zuo a , Larry Baum a, ⁎ a School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong b Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong c Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia d Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia abstract article info Article history: Received 3 September 2011 Accepted 7 December 2011 Available online 16 December 2011 Keywords: Antiepileptic drugs Blood brain barrier Drug resistance Epilepsy P-glycoprotein Structure–activity relationship Epilepsy is the most common serious chronic neurological disorder. Current data show that one-third of pa- tients do not respond to anti-epileptic drugs (AEDs). Most non-responsive epilepsy patients are resistant to several, often all, AEDs, even though the drugs differ from each other in pharmacokinetics, mechanisms of ac- tion, and interaction potential. The mechanisms underlying drug resistance of epilepsy patients are still not clear. In recent years, one of the potential mechanisms interesting researchers is over-expression of P- glycoprotein (P-gp, also known as ABCB1 or MDR1) in endothelial cells of the blood–brain barrier (BBB) in epilepsy patients. P-gp plays a central role in drug absorption and distribution in many organisms. The ex- pression of P-gp is greater in drug-resistant than in drug-responsive patients. Some studies also indicate that several AEDs are substrates or inhibitors of P-gp, implying that P-gp may play an important role in drug resistance in refractory epilepsy. In this article, we review the clinical and laboratory evidence that P- gp expression is increased in epileptic brain tissues and that AEDs are substrates of P-gp in vitro and in vivo. We discuss criteria for identifying the substrate status of AEDs and use structure–activity relationship (SAR) models to predict which AEDs act as P-gp substrates. © 2011 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930 2. The hypothesis that AEDs act as substrates for P-gp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 3. Methods and criteria to identify substrate status of AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 4. The overexpression of P-gp in epilepsy patients and animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933 4.1. In epilepsy patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933 4.2. In animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933 5. AEDs act as substrates of P-gp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934 5.1. In vitro cell models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934 5.2. In vivo animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 5.3. In epilepsy patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 5.4. The substrate status of AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 6. Structure–activity relationship (SAR) between P-gp and AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 7. AEDs induce the overexpression of P-gp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939 8. Proposed further research to determine substrate status of AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940 1. Introduction Epilepsy is the most common serious chronic neurological disorder, affecting more than 50 million people worldwide [1]. It is characterized by recurrent seizures, and is broadly classified into two types: focal or generalized epilepsy. Focal epilepsy causes Advanced Drug Delivery Reviews 64 (2012) 930–942 ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Antiepi- leptic Drug Delivery". ⁎ Corresponding author. Tel.: + 852 39436833; fax: + 852 26035295. E-mail address: lwbaum@cuhk.edu.hk (L. Baum). 0169-409X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.12.003 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr