TY - JOUR
T1 - Propofol metabolism is enhanced after repetitive ketamine administration in rats
T2 - The role of cytochrome P-450 2B induction
AU - Chan, W. H.
AU - Chen, Ta-Liang
AU - Chen, Ruei-Ming
AU - Sun, W. Z.
AU - Ueng, Tzuu-Huei
N1 - Funding Information:
This study was supported in part by a grant NSC94-2314-B-002-141 from the National Science Council R.O.C. and by a grant 93S119 from National Taiwan University Hospital.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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.
AB - 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.
KW - Anaesthetics, i.v., ketamine
KW - Anaesthetics, propofol
KW - Drug-drug interaction
KW - Rat
KW - i.v., enzymes, cytochrome P-450
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U2 - 10.1093/bja/ael173
DO - 10.1093/bja/ael173
M3 - Article
C2 - 16845130
AN - SCOPUS:33748053024
SN - 0007-0912
VL - 97
SP - 351
EP - 358
JO - British Journal of Anaesthesia
JF - British Journal of Anaesthesia
IS - 3
ER -