title: Evidence of carrier-mediated transport in the penetration of donepezil into the rat brain.
abstract: The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL(app,br)) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood-brain barrier (BBB). Consistent with in vivo results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in both MBEC4 cells (i.e., a model for BBB) and HEK 293 cells expressing the transporters found in the brain, indicative of the involvement of organic cation transporters in the transport of the drug. Furthermore, donepezil transport was enhanced (p < 0.01) in HEK 293 cells expressing rOCNT1, rOCTN2, or rCHT1. The CL(app,br) was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CL(app,br) was unaffected with pretreatments with organic cations other than choline, suggesting that choline and donepezil share a common transport mechanism in the penetration across the BBB in vivo. Taken together, these observations suggest that the transport of donepezil across the BBB is mediated by organic cation transporters such as choline transport system(s).
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Seoul National University, San 56-1, Shinlim-dong, Kwanak-gu, Seoul 151-742, Korea.
authors.forename: Mi-Hwa
authors.initials: MH
authors.lastname: Kim
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.forename: Kyung-Ha
authors.initials: KH
authors.lastname: Yu
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002461:Cell Line, Transformed; D002794:Choline / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007189:Indans / Q000493:pharmacokinetics*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D027701:Organic Cation Transport Proteins; D010880:Piperidines; D000077265:Donepezil; D002794:Choline