RRC ID 62228
著者 Yano K, Takimoto S, Motegi T, Tomono T, Hagiwara M, Idota Y, Morimoto K, Takahara A, Ogihara T.
タイトル Role of P-glycoprotein in regulating cilnidipine distribution to intact and ischemic brain.
ジャーナル Drug Metab Pharmacokinet
Abstract Cilnidipine is reported to show antihypertensive and neuroprotective actions in a rat brain ischemia model, but is barely distributed to normal brain, suggesting that its uptake into normal brain is inhibited by efflux transporter(s), such as P-glycoprotein (P-gp). Here, we investigated whether P-gp regulates the brain distribution of cilnidipine. Intracellular accumulation of cilnidipine was decreased in P-gp-overexpressing porcine kidney epithelial cells (LLC-GA5-COL150 cells) compared with control LLC-PK1 cells and the decrease was markedly inhibited by verapamil, a P-gp inhibitor. Further, cilnidipine concentration in the brain of P-gp knockout mice was significantly increased after cilnidipine administration, compared with that in wild-type mice. Moreover, when cilnidipine was administered to male spontaneously hypertensive rats (SHR) with tandem occlusion of the distal middle cerebral and ipsilateral common carotid artery, its concentration in the ischemic hemisphere was 1.6-fold higher than that in the contralateral hemisphere. This result was supported by visualization of cilnidipine distribution using matrix-assisted laser desorption/ionization-time of flight/mass spectrometry (MALDI-TOF/MS) imaging. Our results indicated that cilnidipine is normally excluded from the brain by P-gp-mediated efflux transport, but P-gp function is impaired in ischemic brain and consequently cilnidipine is distributed to the ischemic region.
巻・号 29(3)
ページ 254-8
公開日 2014-1-1
DOI 10.2133/dmpk.dmpk-13-rg-072
PII DN/JST.JSTAGE/dmpk/DMPK-13-RG-072
PMID 24366438
MeSH ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism* Animals Brain / metabolism* Brain Ischemia / metabolism* Carotid Arteries / metabolism Cell Line Dihydropyridines / metabolism* LLC-PK1 Cells Male Mice Middle Cerebral Artery / metabolism Rats Rats, Inbred SHR Swine
IF 2.772
リソース情報
ヒト・動物細胞 LLC-GA5-CoL150(RCB0871)