Received for publication September 9, 2004.
Revised November 5, 2004.
Accepted for publication November 12, 2004.

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 was examined. Tacrine levels in plasma and striatal ECF 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, MPP, TEA and carnitine was inhibited by the addition of tacrine to cultures of mice immortalized brain capillary endothelial cells. In addition, the apical to basal and basal to apical transports of tacrine were inhibited by the addition of organic cations to cultures of LLC-PK1 cells, suggesting that tacrine transport across the BBB is mediated by organic cation transport system(s). Consistent with the in vitro results, a standard RT-PCR procedure was able to amplify the message of mOCT2 and mOCTN2, but not mOCT1, in MBEC4 cells. Similarly, mRNAs for rOCT2 and rOCTN2, were present in representative rat brain samples. To determine whether OCT2 and/or OCTN2 transports tacrine, these transporters were cloned and then transfected in SK-HEP1 and HEK293cells. The uptake of choline, MPP and TEA was inhibited by the presence of tacrine in rOCT2 expressing SK-HEP1 cells while 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 transport across the BBB is mediated, at least in part, by multiple organic cation transport systems in rats.

Key words: blood-brain barrier, drug disposition, organic cation transport, pharmacokinetics