Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 99, Issue 3, Pages 1548-1566Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.21895
Keywords
donepezil; MBEC4; in vitro model; BBB; brain uptake clearance; organic cation transporters
Funding
- Korea Government (MEST) [R01-2007-000-11517-0]
- National Research Foundation of Korea [R01-2007-000-11517-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CLapp,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 CLapp,br was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CLapp,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). (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1548-1566, 2010
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