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タイトル: Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models.
著者: Nakanishi, Haruka
Yonezawa, Atsushi  kyouindb  KAKEN_id
Matsubara, Kazuo  kyouindb  KAKEN_id
Yano, Ikuko  KAKEN_id
著者名の別形: 矢野, 育子
キーワード: Antiepileptic drug
Abcb1
Abcg2
Blood–brain barrier
Knockout mice
Pharmacokinetics
発行日: 15-Jun-2013
出版者: Elsevier B.V.
誌名: European journal of pharmacology
巻: 710
号: 1-3
開始ページ: 20
終了ページ: 28
抄録: 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 60min 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 (Kpbrain) 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 Kpbrain 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 Kpbrain 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.
著作権等: © 2013 Elsevier B.V.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/175253
DOI(出版社版): 10.1016/j.ejphar.2013.03.049
PubMed ID: 23588114
出現コレクション:学術雑誌掲載論文等

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