Received for publication February 23, 2005.
Revised April 22, 2005.
Accepted for publication April 26, 2005.

Neuropharmacokinetics of a new AMPA modulator, S18986, in the rat

Abstract

The aim of our study was to determine the neuropharmacokinetics of S18986, a new positive allosteric modulator of AMPA-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra- and extra-cellular fluid (bICF-bECF) partitioning. BBB transport of S18986 was measured using the in situ brain perfusion technique. bECF concentrations were determined by microdialysis in the two effector areas, i.e. frontal cortex (FC) and dorsal hippocampus (DH), and blood samples were collected simultaneously through a femoral catheter. Cerebrospinal fluid and brain tissue concentrations were determined using a conventional pharmacokinetic approach. Using all the experimental data, pharmacokinetic modelling was applied to describe the S18986 blood-brain disposition. The brain uptake clearance of S18986 was found to be high, about 20 µl s^-1 g^-1. Terminal half-lives were similar in plasma and brain, at around 1 hour. Experimental and predicted blood and brain concentrations were a good fit with the pharmacokinetic model, which assumed first-order rate constants at each interface. Ratios of bECF to the unbound plasma area under the curve (AUC) were 0.24 in FC and 0.25 in DH, whereas ratios of bICF/plasma AUC were 1 in FC and 1.5 in DH. We conclude that despite the ratio of bECF/plasma AUC is below 1, there is nevertheless an elevated BBB uptake of S18986. This can be explained by the S18986 nonhomogenous bECF/bICF partitioning, since S18986 mainly distributes into hippocampal bICF. This illustrates the importance of taking bECF/bICF partitioning into account when interpreting the neuropharmacokinetics of a drug.

Key words: blood-brain barrier, blood-CNS transport, drug distribution, pharmacokinetic modeling, pharmacokinetics