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BJA Advance Access published online on July 15, 2006
British Journal of Anaesthesia, doi:10.1093/bja/ael173
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Accepted April 25, 2006

Laboratory Investigation

Propofol metabolism is enhanced after repetitive ketamine administration in rats: the role of cytochrome P-450 2B induction

W.-H. Chan 1, T.-L. Chen 2, R.-M. Chen 2, W.-Z. Sun 3, and T.-H. Ueng 4 *

1 Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei, Taiwan; Department of Anaesthesia, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan
2 Department of Anaesthesia and Graduate Institute of Medical Science, Taipei Medical University, 250 Wu-Xin Street, Taipei, Taiwan
3 Department of Anaesthesia, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan
4 Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei, Taiwan

* To whom correspondence should be addressed.
T.-H. Ueng, E-mail: thueng{at}ha.mc.ntu.edu.tw


  Abstract

Background. In a series of ex vivo and in vivo studies we investigated the ability of repetitive ketamine administration to alter the metabolism and anaesthetic effect of propofol and the role of ketamine-mediated P-450 2B induction in rats.

Methods. Male Wistar rats were pretreated with 80 mg kg-1 ketamine i.p. twice daily for 4 days. Pentoxyresorufin O-dealkylation (PROD), P-450 2B protein and mRNA were determined. Residual propofol concentration was measured after incubating hepatic microsomes with 100 µM propofol. Sleeping times induced by i.p. 80 mg kg-1 propofol were determined. Orphenadrine, a P-450 2B inhibitor, was added in both ex vivo and in vivo studies. Finally, serial whole blood propofol concentrations were determined after i.v. infusion of 15 mg kg-1 propofol.

Results. Ketamine pretreatment produced 5.4-, 3.4- and 1.7-fold increases in hepatic PROD activity, P-450 2B protein and mRNA, respectively. Residual propofol concentration was 46% lower after incubation with microsomes from ketamine-pretreated rats than in the control group. The addition of orphenadrine to ketamine-pretreated microsomes produced an increase in residual propofol concentration in a concentration-dependent manner. Ketamine pretreatment reduced propofol sleeping time to 12% of the control, which was reversed by orphenadrine. The whole blood propofol concentration in ketamine-pretreated rats was significantly lower than that of control rats at 1, 2, 4 and 8 min after cessation of propofol infusion.

Conclusions. Repetitive ketamine administration enhances propofol metabolism and reduces propofol sleeping time in rats. We suggest that P-450 2B induction may produce ketamine-propofol interaction in anaesthetic practice.

Keywords: anaesthetics, i.v., ketamine; anaesthetics, propofol; drug-drug interaction; i.v., enzymes, cytochrome P-450; rat.
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[Abstract] [Full Text] [PDF]


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