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Antimicrobial Agents and Chemotherapy, September 1998, p. 2178-2183, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Granulocyte Colony-Stimulating Factor Enhances Endotoxin-Induced Decrease in Biliary Excretion of the Antibiotic Cefoperazone in Rats

Masayuki Nadai,¹ Izumi Matsuda,² Li Wang,^3, Akio Itoh,² Kazumasa Naruhashi,⁴ Toshitaka Nabeshima,² Masaki Asai,⁵ and Takaaki Hasegawa^3,*

Laboratory of Clinical Pharmacology and Therapeutics, Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502,¹ Department of Hospital Pharmacy² and Department of Clinical Laboratory,⁵ Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466, Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami Higashi-ku, Nagoya 461,³ and Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-Machi, Kanazawa 920,⁴ Japan

Received 17 November 1997/Returned for modification 2 May 1998/Accepted 10 June 1998

We have recently reported that endotoxin (lipopolysaccharide [LPS]) derived from Klebsiella pneumoniae dramatically decreased the biliary excretion of the -lactam antibiotic cefoperazone (CPZ), which is primarily excreted into the bile via the anion transport system, in rats. The present study was designed to investigate the effect of human recombinant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharmacokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of body weight) was administered intravenously 2 h after the intravenous injection of LPS (250 µg/kg). G-CSF was injected subcutaneously at 12 µg/kg for 3 days and was administered intravenously at a final dose of 50 µg/kg 1 h before LPS injection. Peripheral blood cell numbers were also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enhanced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in the controls, while the total leukocyte numbers were decreased (about 3,000 cells/µl) by treatment with LPS. Pretreatment with G-CSF produces a deleterious effect against the LPS-induced decrease in biliary secretion of CPZ, and leukocytes play an important role in that mechanism.

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^* Corresponding author. Mailing address: Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya 461-8673, Japan. Phone: 81-52-719-1558. Fax: 81-52-719-1506.

Present address: Department of Pharmacology, School of Pharmacy, West China University of Medical Sciences, Chengdu, China.

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Antimicrobial Agents and Chemotherapy, September 1998, p. 2178-2183, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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