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Antimicrobial Agents and Chemotherapy, November 1999, p. 2697-2701, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Decreased Antipyrine Clearance following Endotoxin Administration: In Vivo Evidence of the Role of Nitric Oxide

Kiyoyuki Kitaichi,1 Li Wang,1,2 Kenji Takagi,1 Mitsunori Iwase,1 Eiji Shibata,1 Masayuki Nadai,3 Kenzo Takagi,1 and Takaaki Hasegawa1,*

Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya 461-8673,1 and Laboratory of Pharmaceutics, Faculty of Pharmacy, Meijo University, Nagoya 468-8503,3 Japan, and The First University Hospital, West China University of Medical Sciences, Chengdu 610041, China2

Received 8 February 1999/Returned for modification 10 June 1999/Accepted 30 August 1999

Klebsiella pneumoniae endotoxin has been found to decrease hepatic P450-mediated drug-metabolizing enzyme activity in a time-dependent manner. In this study, we investigated the role of nitric oxide (NO) in the decrease in hepatic drug-metabolizing enzyme activity caused by endotoxin in vivo. We measured in vivo pharmacokinetic parameters of antipyrine in rats treated with endotoxin and/or a selective inhibitor of inducible NO synthase (iNOS), S-methylisothiourea. Intraperitoneal injection of endotoxin (1 mg/kg of body weight) dramatically decreased the systemic clearance of antipyrine, reflecting reduced hepatic drug-metabolizing enzyme activity, and significantly increased the level of nitrite and nitrate (NOx) in the plasma. S-Methylisothiourea (10 mg/kg) reversed this decreasing antipyrine clearance and reduced the level of NOx in plasma. Repeated injections of an NO donor, (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409; 10 mg/kg), at a dose which maintained plasma NOx at the same levels as those caused by endotoxin injection, also decreased the systemic clearance of antipyrine. These findings suggest that the overproduction of NO observed in this animal model is at least partially responsible for the significant reduction in the hepatic drug-metabolizing enzyme activity that may happen in a gram-negative bacterial infection.

* Corresponding author. Mailing address: Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya 461-8763, Japan. Phone: 81 52 719 1558 1341. Fax: 81 52 719 3009. E-mail: hasegawa{at}met.nagoya-u.ac.jp.

Antimicrobial Agents and Chemotherapy, November 1999, p. 2697-2701, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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