TY - JOUR T1 - NEUROPHARMACOKINETICS OF A NEW α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC ACID (AMPA) MODULATOR, S18986 [(<em>S</em>)-2,3-DIHYDRO-[3,4]CYCLOPENTANO-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE], IN THE RAT JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1137 LP - 1143 DO - 10.1124/dmd.105.004424 VL - 33 IS - 8 AU - Fanchon Bourasset AU - Katy Bernard AU - Carmen Muñoz AU - Patrick Genissel AU - Jean-Michel Scherrmann Y1 - 2005/08/01 UR - http://dmd.aspetjournals.org/content/33/8/1137.abstract N2 - The aim of our study was to determine the neuropharmacokinetics of S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], a new positive allosteric modulator of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra- and extracellular 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 modeling 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 h. 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 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. The American Society for Pharmacology and Experimental Therapeutics ER -