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Antimicrobial Agents and Chemotherapy, December 1998, p. 3136-3140, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Possible Mechanism by Which the Carbapenem Antibiotic Panipenem Decreases the Concentration of Valproic Acid in Plasma in Rats

Saori Kojima,1 Masayuki Nadai,2 Kiyoyuki Kitaichi,3 Li Wang,4 Toshitaka Nabeshima,1 and Takaaki Hasegawa3,*

Department of Hospital Pharmacy, Nagoya University School of Medicine, Nagoya 466,1 Laboratory of Clinical Pharmacology and Therapeutics, Gifu Pharmaceutical University, Gifu 502,2 and Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya 461,3, Japan, and Department of Pharmacology, School of Pharmacy, West China University of Medical Sciences, Chengdu 610041, Sichuan, China4

Received 1 December 1997/Returned for modification 2 August 1998/Accepted 1 September 1998

There is evidence indicating that the carbapenem antibiotic panipenem decreases plasma concentrations of valproic acid (VPA) in epileptic patients during VPA therapy. The mechanism for panipenem-induced changes in the pharmacokinetics of VPA was investigated in rats with and without bile duct cannulation. The effect of panipenem on the pharmacokinetics of diclofenac, which undergoes extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of body weight) or diclofenac (10 mg/kg of body weight) was administered intravenously under the steady-state plasma panipenem concentration of 4 µg/ml, which had been achieved by a constant infusion rate. Panipenem decreased the plasma VPA concentrations in rats without bile duct cannulation but did not change the volume of the initial space and protein binding of VPA. However, panipenem had no effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in plasma diclofenac concentration observed in the absence of panipenem was diminished in the presence of panipenem. These findings suggest that panipenem decreases plasma VPA concentrations by suppressing its enterohepatic recirculation, probably due to a panipenem-induced decrease in the numbers of enteric bacteria.

* 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 or 1509. E-mail: hasegawa{at}met.nagoya-u.ac.jp.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3136-3140, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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