Abstract
This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (Cu,plasma) to predict brain unbound concentration (Cu,brain). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The Cu,brain was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of Cu,brain/CCSF and Cu,brain/Cu,plasma were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had Cu,brain/CCSF and Cu,brain/Cu,plasma ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl-]sarcosine, had Cu,brain/CCSF and Cu,brain/Cu,plasma ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, CCSF and Cu,plasma represent Cu,brain equally well; for efflux substrates or slow brain penetration compounds, CCSF appears to be equivalent to or more accurate than Cu,plasma to represent Cu,brain. Thus, we hypothesize that CCSF is equivalent to or better than Cu,plasma to predict Cu,brain. This hypothesis is supported by the literature data.
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.105.008201.
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ABBREVIATIONS: CNS, central nervous system; BBB, blood-brain barrier; CSF, cerebrospinal fluid; BCSFB, blood-CSF barrier; P-gp, P-glycoprotein; CCSF, CSF drug concentration; Cu,plasma, plasma unbound drug concentration; Cu,brain, brain unbound drug concentration; AUC, area under the curve; NFPS, N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine; CP-141938, methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide; HPLC, high-performance liquid chromatography.
- Received November 4, 2005.
- Accepted May 23, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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