Propofol ,etabolism is enhanced after
repetitive ketamine administration in
rats: the role of cytochrome P-450 2B
induction
陳大樑
Chan WH;Chen TL;Chen RM;Sun WZ;Ueng TH
摘要
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.
reduces propofol sleeping time in rats. We suggest that P-450 2B induction may produce ketamine–propofol interaction in anaesthetic practice.
