Abstract
The distribution of HSR-903, a new quinolone antibacterial agent, to the brain after i.v. administration to rats was low compared with that to other tissues. The blood-brain barrier permeability to HSR-903 determined by the brain perfusion method was low, and increased nonlinearly with increasing concentration of HSR-903 in the perfusate. When the brain-to-plasma concentration ratio (Kp,brain) was measured in mdr1a gene-knockout mice, the value was 8 times higher than that in normal mice. The uptake of [14C]HSR-903 by multidrug-resistant K562/ADM cells, which express P-glycoprotein (P-gp), was significantly lower than that by the drug-sensitive parent K562 cells. In addition, the uptake of [14C]HSR-903 by K562/ADM cells was significantly increased in the presence of cyclosporin A and ATP-depleting agents. These observations support the idea that P-gp participates in HSR-903 efflux from the brain. The steady-state uptake of HSR-903 by a monolayer of primary cultured bovine brain capillary endothelial cells was increased in the presence of several quinolone antibacterial agents or anionic compounds, such as 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, and in bicarbonate ion-free medium, as well as by P-gp inhibitors (cyclosporin A and quinidine). These results suggested that the efflux of HSR-903 proceeds at least partly via an anion-sensitive efflux transport mechanism as well as via P-gp. In conclusion, the low brain distribution of the new quinolone antibacterial agent HSR-903 can be ascribed to multiple efflux mechanisms including P-gp and an unidentified anion-sensitive transporter operating in the brain capillary endothelial cells that constitute the blood-brain barrier.
Footnotes
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Send reprint requests to: Dr. Akira Tsuji, Department of Pharmacobio-dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan. E-mail:tsuji{at}kenroku.kanazawa-u.ac.jp
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↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture and by the Japan Research Foundation for Clinical Pharmacology, Japan.
- Abbreviations:
- P-gp
- P-glycoprotein
- MDR
- multidrug-resistant
- MRP
- multidrug resistance-associated protein
- BBB
- blood-brain barrier
- BCECs
- brain capillary endothelial cells
- Kp
- tissue-to-plasma concentration ratio
- Kp,brain
- brain-to-plasma concentration ratio
- DIDS
- 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid
- SITS
- 4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid
- BEI
- brain efflux index
- Received February 8, 1999.
- Accepted March 31, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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