Kinetic Evidence for Active Efflux Transport across the Blood-Brain Barrier of Quinolone Antibiotics1
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan
Abstract
A distributed model has been used to clarify the mechanism of the restricted and differential distribution of the quinolone antibiotics in the rat central nervous system (CNS). The symmetrical permeability clearances across the blood-brain barrier (BBB), PSBBB, and across the blood-cerebrospinal fluid barrier (BCSFB), PSCSF, and the active efflux clearances across the BBB, PSBBB,eff, were obtained from a nonlinear least squares regression analysis combined with the fast inverse Laplace transforming program for invivo data. The values of PSBBB,eff were 10- to 260-fold greater than those of PSBBB, providing kinetic evidence to support the hypothesis that a significant efflux transport across the BBB is responsible for the limited distribution of quinolones in brain tissue. Moreover, by simulation studies, we could demonstrate the concentration profiles in the brain as a function of the distance from the ependymal surface. However, active efflux transport across the BCSFB has been suggested to have only a slight effect on the apparent elimination from the cerebrospinal fluid. Comparing the apparent brain tissue-to-unbound serum concentration ratio at steady state, it has been suggested that the net flux across the BBB, i.e., the ratio of PSBBB to the sum of PSBBB and PSBBB,eff, is a determinant for the differential distribution of these quinolones in brain tissue. Such a putative active efflux transport system would play a significant role in decreasing the brain interstitial fluid concentration of quinolones.
Footnotes
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Send reprint requests to: Yuichi Sugiyama, Ph.D., Professor, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan.
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↵1 This research was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and the Research Fund from the Human Science Foundation.
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↵2 Present address: Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi 329–01, Japan.
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↵3 Present address: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980–77, Japan.
- Abbreviations:
- CNS
- central nervous system
- GABA
- γ-aminobutyric acid
- CSF
- cerebrospinal fluid
- ISF
- interstitial fluid
- BBB
- blood-brain barrier
- BCSFB
- blood-CSF barrier
- NFLX
- norfloxacin
- OFLX
- ofloxacin
- FLRX
- fleroxacin
- PFLX
- pefloxacin
- AM-1155
- (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid
- SPFX
- sparfloxacin
- HPLC
- high-performance liquid chromatography
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- Received January 6, 1997.
- Accepted June 10, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
