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Antimicrobial Agents and Chemotherapy, July 1998, p. 1738-1744, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

P-Glycoprotein-Mediated Transport of Itraconazole across the Blood-Brain Barrier

Tetsuo Miyama,1 Hitomi Takanaga,1 Hirotami Matsuo,1 Katsuhiro Yamano,2 Koujirou Yamamoto,2 Tatsuji Iga,2 Mikihiko Naito,3 Takashi Tsuruo,3 Hitoshi Ishizuka,4 Yukinori Kawahara,4 and Yasufumi Sawada1,*

Faculty of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582,1 Department of Pharmacy, Faculty of Medicine, The University of Tokyo Hospital,2 and Institute of Molecular and Cellular Biosciences,3 University of Tokyo, Bunkyo-ku, Tokyo 113-8655, and Analytical and Metabolic Research Laboratories, Sankyo Co. Ltd., Shinagawa-ku, Tokyo 140-8710,4 Japan

Received 10 June 1997/Returned for modification 22 November 1997/Accepted 2 March 1998

The mechanism for the accumulation of itraconazole (ITZ) in its elimination from the brain was studied in rats and mice. The concentration of ITZ in liver tissue declined in parallel with the plasma ITZ concentration until 24 h after intravenous injection of the drug (half-life, 5 h); however, the ITZ in brain tissue rapidly disappeared (half-life, 0.4 h). The time profiles of the brain/plasma ITZ concentration ratio (Kp value) showed a marked overshooting, and the Kp value increased with increasing dose; these phenomena were not observed in the liver tissue. This finding indicates the occurrence of a nonlinear efflux of ITZ from the brain to the blood. Moreover, based on a pharmacokinetic model which hypothesized processes for both nonlinear and linear effluxes of ITZ from the brain to the blood, we found that the efflux rate constant in the saturable process was approximately sevenfold larger than that in the nonsaturable process. The Kp value for the brain tissue was significantly increased in the presence of ketoconazole or verapamil. The brain Kp value for mdr1a knockout mice was also significantly increased compared with that of control mice. Moreover, the uptake of vincristine or vinblastine, both of which are substrates of the P glycoprotein (P-gp), into mouse brain capillary endothelial cells was also significantly increased by ITZ or verapamil. In conclusion, P-gp in the brain capillary endothelial cells participates in a process of active efflux of ITZ from the brain to the blood at the blood-brain barrier, and ITZ can be an inhibitor of various substrates of P-gp.

* Corresponding author. Mailing address: Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6610. Fax: 81-92-642-6614. E-mail: yasufumi{at}yakuzai.phar.kyushu-u.ac.jp.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1738-1744, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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