Plasma Levels of Ketamine and Two of Its Metabolites in Surgical Patients Using a Gas Chromatographic Mass Fragmentographic Assay

Domino, Edward F.; Zsigmond, Elemér K.; Domino, Laurence E.; Domino, Kenneth E.; Kothary, Sarla P.; Dominof, Steven E.

doi:10.1213/00000539-198202000-00004

Cited by 150 publications

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“…Administration of neither 25, 50, nor 100 M ketamine was cytotoxic to HepG2 cells. Concentrations of ketamine used in this study are within the range of clinical relevance (Domino et al, 1982;Grant et al, 1983). Under such clinically relevant concentrations, ketamine suppressed polymerization of F-actin and microtubular cytoskeletons.…”

Section: Discussionmentioning

confidence: 99%

“…Ketamine was dissolved in phosphate-buffered saline (0.14 M NaCl, 2.6 mM KCl, 8 mM Na 2 HPO 4 , and 1.5 mM KH 2 PO 4 ). Concentrations of ketamine (Յ100 M), which correspond to clinical plasma concentrations (Domino et al, 1982;Grant et al, 1983), were chosen as the treated dosages in this study. To avoid drug interaction, when HepG2 cells were exposed to ketamine, the culture medium did not contain serum and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

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Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang¹,

Chen²,

Chen

2008

Drug Metab Dispos

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ABSTRACT:Ketamine is an intravenous anesthetic agent often used for inducing and maintaining anesthesia. Cytoskeletons contribute to the regulation of hepatocyte activity of drug biotransformation. In this study, we attempted to evaluate the effects of ketamine on F-actin and microtubular cytoskeletons in human hepatoma HepG2 cells and its possible molecular mechanisms. Exposure of HepG2 cells to ketamine at <100 M, which corresponds to clinically relevant concentrations for 1, 6, and 24 h, did not affect cell viability. Meanwhile, administration of therapeutic concentrations of ketamine obviously interrupted F-actin and microtubular cytoskeletons. In parallel, levels of intracellular calcium concentration-and timedependently decreased after ketamine administration. Analysis by confocal microscopy further revealed that ketamine suppressed calcium mobilization from an extracellular buffer into HepG2 cells.Exposure to ketamine decreased cellular ATP levels. The mitochondrial membrane potential and complex I NADH dehydrogenase activity were both reduced after ketamine administration. Ketamine did not change the production of actin or microtubulin mRNA in HepG2 cells. Consequently, ketamine-caused cytoskeletal interruption led to suppression of CYP3A4 expression and its metabolizing activity. Therefore, this study shows that therapeutic concentrations of ketamine can disrupt F-actin and microtubular cytoskeletons possibly through suppression of intracellular calcium mobilization and cellular ATP synthesis due to downregulation of the mitochondrial membrane potential and complex I enzyme activity. Such disruption of the cytoskeleton may lead to reductions in CYP3A4 activity in HepG2 cells.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang¹,

Chen²,

Chen

2008

Drug Metab Dispos

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“…Ketamine has been used extensively as an anesthetic agent and the plasma concentrations associated with subanesthetic psychosislike perceptual disturbances are in the range of 0.5-1 M, 28 and with anesthesia setting in at concentrations in the 10-100 M range. [29][30][31] Further, brain concentrations are known to be several fold higher than plasma concentrations, 32 suggesting that even the subanesthetic psychosis-like perceptual disturbances occur only at brain concentrations in the one to few micromolar range. Since the affinities of ketamine for the NMDA receptors as well as for the dopamine D 2 and serotonin 5-HT 2 are relevant in this M range, this would make a selective disruption of NMDA transmission by these agents unlikely.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

2002

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“…Plasma ketamine concentrations were comparatively stable during anaesthesia using a fixed infusion rate of 25ngkg~'min~1 ( fig. 1) and were approximately twice the value at which consciousness has been noted to return (Idvall et al, 1979;Domino et al, 1982). None of the patients who received ketamine experienced any emergence reactions during recovery from anaesthesia and all were willing to have the same anaesthetic technique again if required.…”

Section: Discussionmentioning

confidence: 89%

Effects of Ketamine Anaesthesia on the Metabouc Response to Pelvic Surgery

Lacoumenta

Walsh

Waterman

et al. 1984

British Journal of Anaesthesia

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SUMMARYThe effects of ketamine anaesthesia on the metabolic and endocrine response to pelvic surgery were investigated, and compared with results obtained in a control group of patients anaesthetized with thiopentone and halo thane. Ketamine anaesthesia before the onset of surgery was associated with a significant increase in blood glucose and plasma cortisol concentrations, and in heart rate. However, when surgery was established there were no metabolic, endocrine or haemodynamic differences between ketamine and halothane anaesthesia. We conclude that ketamine does not exacerbate the metabolic response to surgery.Although the cardiovascular effects of ketamine anaesthesia have been studied in detail (for review see White, Way and Trevor, 1982), little attention has been directed towards the associated endocrine and metabolic changes. Since it has been shown that ketamine causes an increase in circulating catecholamine (Takki et al., 1972;Baraka, Harrison and Kachachi, 1973; Appeletal., 1979), ACTHand cortisol concentrations (Oyama, Matsumoto and Kudo, 1970), it could be argued that the use of this agent may exacerbate the metabolic response to surgery.Clarke and colleagues (1974) found that ketamine anaesthesia was associated with slightly higher blood glucose and plasma cortisol concentrations, when compared with other induction agents in patients who had undergone minor gynaecological surgery. In contrast, Kaniaris and co-workers (1975) demonstrated a decreased glucose and nonesterified fatty acid (NEFA) response to surgery with ketamine anaesthesia compared with halothane and thiopentone in children. In a recent study by Stefansson, Wickstrom and Haljamae (1982a) ketamine anaesthesia was used in elderly patients undergoing surgical correction of fractured neck of femur and changes in circulating and intramuscular metabolites were measured. Unfortunately, a direct comparison of these metabolic results with similar patients anaesthetized with other techniques was not possible because of differences in the preoperative blood glucose concentration (Stefansson, Wickstrom and Haljamae, 1982b, c).In the present study we have attempted to resolve these conflicting reports by examining the effects of ketamine anaesthesia on the concentrations of circulating metabolites, and cortisol, during pelvic surgery. PATIENTS AND METHODSSixteen healthy women admitted for Fallopian tubal surgery were investigated. On admission to hospital their height and body weight were recorded and the body mass index calculated as an estimate of adiposity (Keys, Fidanza and Karvonen, 1972). The patients were allocated randomly to receive supplementation of anaesthesia either with an infusion of ketamine, or with halothane. The nature of the study was explained to the patients and consent obtained for the collection of samples of central venous blood.All patients were premedicated with papaveretum 15-20mg and hyoscineO.3-0.4mgi.m. 90min before surgery. On arrival in the anaesthetic room the duration of starvation was determined and a centr...

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Plasma Levels of Ketamine and Two of Its Metabolites in Surgical Patients Using a Gas Chromatographic Mass Fragmentographic Assay

Cited by 150 publications

References 0 publications

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

Effects of Ketamine Anaesthesia on the Metabouc Response to Pelvic Surgery

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