Abstract
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.
Footnotes
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This work was supported by the Institut de Recherches Internationales Servier (IRIS), Courbevoie, France, and by the Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.004424.
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ABBREVIATIONS: S18986, (S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; BBB, blood-brain barrier; bECF, brain extracellular fluid; CSF, cerebrospinal fluid; bICF, brain intracellular fluid; HPLC, high-performance liquid chromatography; FC, frontal cortex; DH, dorsal hippocampus; AUC, area under the curve.
- Received February 22, 2005.
- Accepted April 26, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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