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JAC Advance Access published online on May 26, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh255
© 2004 by The British Society for Antimicrobial Chemotherapy
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Received February 20, 2004
Revised March 22, 2004
Accepted April 1, 2004

Original article

Pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect of imipenem in rats with experimental hypovolaemia or endotoxaemia

A. Limosin 1, A. Dupuis 2, I. Lamarche 3, O. Mimoz 4, J. Paquereau 5, W. Couet 3*

1 EE Médicaments Anti-infectieux et Barrière Hémato-encéphalique, Poitiers Cedex, France Laboratoire de Pharmacocinétique, PBS, Poitiers Cedex, France
2 EE Médicaments Anti-infectieux et Barrière Hémato-encéphalique, Poitiers Cedex, France Pharmacie Centrale, CHU La Milétrie, 86022 Poitiers, France
3 EE Médicaments Anti-infectieux et Barrière Hémato-encéphalique, Poitiers Cedex, France
4 EE Médicaments Anti-infectieux et Barrière Hémato-encéphalique, Poitiers Cedex, France Département d'Anesthésie et Réanimation Chirurgicale, CHU La Milétrie, 86000 Poitiers Cedex, France
5 Equipe Sommeil: Attention et Respiration, PBS, Faculté de Médecine & Pharmacie, 40 avenue du Recteur Pineau, 86022 Poitiers Cedex, France

* To whom correspondence should be addressed. E-mail: william.couet{at}univ-poitiers.fr.


  Abstract

Objectives: The epileptogenic activity of imipenem in rats with experimentally induced hypovolaemia or endotoxaemia was investigated by pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect.

Methods: Hypovolaemia was induced by removal of 30% of the blood volume and endotoxaemia by intravenous lipopolysaccharide injection.

Results: Imipenem clearance and volume of distribution values of 16.4±1.1 mL/min per kg and 357±49 mL/kg (mean±S.E.M.) in healthy rats (n=5), were significantly reduced in hypovolaemic (n=6) and endotoxaemic (n=6) animals. A dose reduction from 250 mg/kg to 120 mg/kg was necessary in endotoxaemic rats. The pharmacokinetic-pharmacodynamic model with an effect compartment previously developed in healthy rats described the data adequately and pharmacodynamic parameters in hypovolaemic and endotoxaemic rats were not significantly different from corresponding values estimated in the control group.

Conclusion: Hypovolaemia and endotoxaemia only had an effect on imipenem pharmacokinetics.

Key Words: Keywords: carbapenems, EEG, epileptogenic


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