Abstract
The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (Cub), cerebral spinal fluid concentration (CCSF), and unbound plasma concentration (Cup) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (Cm). Nine compounds—carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental—were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1–9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the Cubs were within 3-fold of their Cm; thiopental had a Cm 4-fold of its Cub. The CCSFs of eight of the nine compounds were within 3-fold of their corresponding Cm; 9-hydroxyrisperidone showed a CCSF 5-fold of its Cm. The Cups of five of the nine compounds were within 3-fold of their Cm; four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had Cups 6- to 14-fold of their Cm. In conclusion, the Cub and CCSF were within 3-fold of the Cm for the majority of the compounds tested. The Cups were within 3-fold of Cm for lipophilic non–P-glycoprotein (–P-gp) substrates and greater than 3-fold of Cm for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.
Footnotes
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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.108.024125.
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ABBREVIATIONS: Cup, unbound plasma concentration; BBB, blood-brain barrier; BCSFB, blood-cerebrospinal fluid barrier; Cm, unbound brain interstitial fluid concentration measured by brain microdialysis; CSF, cerebral spinal fluid; Cub, unbound brain concentration measured by brain homogenate method; CCSF, CSF concentration; P-gp, P-glycoprotein; HPLC/MS/MS, high-performance liquid chromatography combined with tandem mass spectrometry; KO, knockout; WT, wild type; CP-122721, (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine.
- Received August 22, 2008.
- Accepted December 29, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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