title: Role of P-glycoprotein in regulating cilnidipine distribution to intact and ischemic brain.
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.
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yano
authors.forename: Shinobu
authors.initials: S
authors.lastname: Takimoto
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Motegi
authors.forename: Takumi
authors.initials: T
authors.lastname: Tomono
authors.forename: Mihoko
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Idota
authors.forename: Kaori
authors.initials: K
authors.lastname: Morimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism; D002460:Cell Line; D004095:Dihydropyridines / Q000378:metabolism*; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D020768:Middle Cerebral Artery / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004095:Dihydropyridines; C065927:cilnidipine