Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models

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• 作者：Haruka Nakanishi^a ; Atsushi Yonezawa^b ; Kazuo Matsubara^b ; Ikuko Yano^a ; ^{iyano@kuhp.kyoto-u.ac.jp}
• 关键词：Antiepileptic drug ; Abcb1 ; Abcg2 ; Blood&ndash ; brain barrier ; Knockout mice ; Pharmacokinetics
• 刊名：European Journal of Pharmacology
• 出版年：2013
• 出版时间：15 June, 2013
• 年：2013
• 卷：710
• 期：1-3
• 页码：20-28
• 全文大小：900 K

文摘

Refractory epilepsy is reportedly associated with an overexpression of ATP-binding cassette transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (Bcrp). In this study, we examined the contribution of Pgp and Bcrp to the brain distribution of 12 antiepileptic drugs (AEDs) in Mdr1a/1b(?/?) and Mdr1a/1b(?/?)/Bcrp(?/?) mice within a therapeutic concentration range. The blood concentrations were sequentially determined, and the brain concentrations were measured at 60 min after intravenous administration. The plasma concentration profiles for each AED in the Mdr1a/1b(?/?) mice were equivalent to those in the wild-type mice. In contrast, the plasma concentration profiles of phenytoin, lamotrigine, topiramate, tiagabine, and levetiracetam in the Mdr1a/1b(?/?)/Bcrp(?/?) mice were significantly lower than the corresponding ones in the wild-type mice. The brain-to-plasma concentration ratio (Kp_brain) values of phenytoin, topiramate, and tiagabine in the Mdr1a/1b(-/-) mice were significantly higher than the corresponding ones in the wild-type mice. In contrast, the Kp_brain values of phenobarbital, clobazam, zonisamide, gabapentin, tiagabine, and levetiracetam in the Mdr1a/1b(?/?)/Bcrp(?/?) mice were significantly higher than the corresponding ones in Mdr1a/1b(?/?) mice. The Kp_brain values of the 12 AEDs in the Mdr1a/1b(?/?)/Bcrp(?/?) mice, but not wild-type mice, significantly correlated with the corresponding molecular weight values. These findings suggest that both Pgp and Bcrp restrict brain access for several AEDs. Taken together, information on the contribution of each transporter may be useful in the development of strategic treatments of refractory epilepsy.