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BJA Advance Access originally published online on July 15, 2006
British Journal of Anaesthesia 2006 97(3):351-358; 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

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

W.-H. Chan1,2, T.-L. Chen3, R.-M. Chen3, W.-Z. Sun2 and T.-H. Ueng1,*

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

*Corresponding author. E-mail: thueng{at}ha.mc.ntu.edu.tw

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.


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