Propofol metabolism is enhanced after repetitive ketamine administration in rats

The role of cytochrome P-450 2B induction

W. H. Chan, Ta-Liang Chen, Ruei-Ming Chen, W. Z. Sun, Tzuu-Huei Ueng

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)351-358
Number of pages8
JournalBritish Journal of Anaesthesia
Volume97
Issue number3
DOIs
Publication statusPublished - Sep 2006

Fingerprint

Ketamine
Propofol
Cytochrome P-450 Enzyme System
Orphenadrine
Microsomes
Dealkylation
Anesthetics
Messenger RNA
Liver
Wistar Rats
Proteins

Keywords

  • Anaesthetics, i.v., ketamine
  • Anaesthetics, propofol
  • Drug-drug interaction
  • i.v., enzymes, cytochrome P-450
  • Rat

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Propofol metabolism is enhanced after repetitive ketamine administration in rats : The role of cytochrome P-450 2B induction. / Chan, W. H.; Chen, Ta-Liang; Chen, Ruei-Ming; Sun, W. Z.; Ueng, Tzuu-Huei.

In: British Journal of Anaesthesia, Vol. 97, No. 3, 09.2006, p. 351-358.

Research output: Contribution to journalArticle

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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.",
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