title: Saturable distribution of tacrine into the striatal extracellular fluid of the rat: evidence of involvement of multiple organic cation transporters in the transport.
abstract: The kinetics and mechanism by which tacrine is distributed in the rat brain were examined. Tacrine levels in plasma and striatal extracellular fluid were used to evaluate the pharmacokinetics of this process. The K(D,brain) was decreased with the dose for tacrine, indicating that the distribution to the brain is saturable. The uptake of organic cations such as choline, 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), and carnitine was inhibited by the addition of tacrine to cultures of mouse immortalized brain capillary endothelial cells. In addition, the apical to basal transport and basal to apical transport of tacrine were inhibited by the addition of organic cations to cultures of LLC-PK1 cells, suggesting that tacrine transport across the blood-brain barrier (BBB) is mediated by organic cation transport system(s). Consistent with the in vitro results, a standard reverse transcription-polymerase chain reaction procedure was able to amplify the message of mOCT2 and mOCTN2, but not mOCT1, in MBEC4 (mouse brain microvessel endothelial cell line 4) cells. Similarly, mRNAs for rOCT2 and rOCTN2 were present in representative rat brain samples. To determine whether OCT2 and/or OCTN2 transport tacrine, these transporters were cloned and then transfected in SK-HEP1 and HEK 293 cells. The uptake of choline, MPP, and TEA was inhibited by the presence of tacrine in rOCT2-expressing SK-HEP1 cells, whereas the uptake of carnitine was inhibited by the presence of tacrine in rOCTN2-expressing HEK 293 cells. Collectively, these observations suggest that the transport of tacrine across the BBB is mediated, at least in part, by multiple organic cation transport systems in rats.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Seoul National University, San 56-1 Shinlim-dong, Kwanak-gu, Seoul 151-742 Korea.
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Sung
authors.forename: Kyung-Ha
authors.initials: KH
authors.lastname: Yu
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Park
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; D001692:Biological Transport; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D003342:Corpus Striatum / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074058:Solute Carrier Family 22 Member 5; D013619:Tacrine / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002800:Cholinesterase Inhibitors; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger; C491012:Slc22a2 protein, mouse; C100590:Slc22a2 protein, rat; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D013619:Tacrine