BJA Advance Access originally published online on January 11, 2007
British Journal of Anaesthesia 2007 98(2):204-212; doi:10.1093/bja/ael336
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Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies
1 Anaesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, Bern, Switzerland
2 Pharmacology Department, Veterinary Faculty, La Plata University, Argentina
3 Department of Clinical Pharmacology, University of Bern, Switzerland
* Corresponding author: Department of Clinical Pharmacology, Murtenstrasse 35, CH-3010 Bern, Switzerland. E-mail: wolfgang.thormann{at}ikp.unibe.ch
Accepted for publication November 13, 2006.
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BACKGROUND: The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval).
METHODS: Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2 mg kg–1) or S-ketamine (1.1 mg kg–1) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128 min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, Cmax, and Tmax. Pulse rate (PR), respiratory rate (Rf), tidal volume (VT), minute volume ventilation (VE), end-tidal partial pressure of carbon dioxide (PE'CO2), and mean arterial blood pressure (MAP) were also evaluated.
RESULTS: The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and Cmax were found for S-norketamine compared with R-norketamine in the racemic group. Overall, Rf, VE, PE'CO2, and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group.
CONCLUSIONS: Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigation.
Keywords: anaesthetics, i.v., ketamine; pharmacokinetics, ketamine; stereoisomers, capillary electrophoresis
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The rational use of ketamine, alone or in combination with volatile anaesthetics, relies on the knowledge of its disposition within the body, so that dose recommendations can be established and adjusted according to the desired blood or plasma drug levels. Although the disposition of ketamine is well documented in horses,1–4 only one study reports the plasma levels of ketamine and norketamine enantiomers obtained after racemic (R-/S-) ketamine i.v. administration for anaesthesia induction in this species.5 This study showed higher plasma levels of S-norketamine than R-norketamine, suggesting that N-demethylation might be highly enantioselective in horses. The potential for discrimination between enantiomers at different stages of drug metabolism is therefore important and highlights the need for stereospecific drug assays.6
In humans and mice, the S-enantiomer has been proven advantageous, reaching an identical depth of anaesthesia with only half of the necessary racemic dose.7–9 Differences in the metabolism of the ketamine enantiomers after R-/S-ketamine administration when compared with the sole S-ketamine administration might partially explain the faster recovery of the psychomotor function observed when S-ketamine is given alone.9–12
As a prelude to studying ketamine infusions in horses, the main goal of this study was to determine the pharmacokinetic profile of ketamine enantiomers after a single i.v. bolus of either R-/S-ketamine or S-ketamine in healthy ponies under isoflurane anaesthesia.
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Study design and animals
The experiments were performed with permission of the committee for animal experimentation, Bern, Switzerland. The experimental trial was designed as a randomized prospective 2-month interval cross-over study. Seven experimental, 4 year-old, Shetland pony geldings, mean weight 122 kg (SD 16 kg), were included in this study. The ponies were administered first R-/S-ketamine (RS-k) and after 2 months of wash-out interval, S-ketamine (S-k). They were conventionally housed as a group at the equine clinic of the Vetsuisse-Faculty (Bern, Switzerland). The animals had their right carotid artery surgically elevated to allow easy access by percutaneous puncture about 2 yr before this experiment and were judged healthy on the basis of physical examination, complete blood count and biochemistry profile. On the day before the experiment, ponies were housed in a separate box to allow withholding of food for 24 h. Access to water was granted until 1 h prior to the study.
Anaesthesia and instrumentation
The whole animal experimental phase was conducted in a padded recovery stall to both induce anaesthesia and allow for a safe anaesthetic recovery. A broad rope to restrain horses was placed around the ponies' pectoralis region, then passed around their hind quarters below their quadriceps and anchored to itself over the left side of their chest. After protective bandaging of the extremities, an additional rope was placed around every metacarpus/metatarsus. By pulling and stretching the ropes gently, the ponies were smoothly placed in right lateral recumbency and restrained in that position until anaesthesia induction was achieved. Ponies were trained to be restrained with this technique from prior studies.13 Anaesthesia was then induced with isoflurane in oxygen (O2) via a hermetically closed face mask connected to a small-animal anaesthesia circle system (Roche Electronic Respirator 3100, F. Hoffmann-La Roche, Basel, Switzerland). The vaporizer was first set to 1% and isoflurane delivery started via the face mask (O2 flow: 6 litres min–1) and gradual increments of 0.5% were made over 5 min until the ponies reached an appropriate anaesthetic plane for endotracheal intubation (muscle relaxation, eyeball rotation, reduced palpebral reflex, absence of swallowing reflex). Subsequently, a 14 mm ID cuffed rubber–silicone tube was placed into their tracheas and connected to the breathing system. Ponies were let to breathe spontaneously throughout the whole procedure. In the event of apnoea longer than 30 s, intermittent positive pressure ventilation (IPPV) was applied by manually squeezing the reservoir bag of the breathing system twice per minute until spontaneous ventilation was restored. Anaesthesia was maintained with isoflurane in O2 throughout the whole experiment, at each pony's predetermined individual minimum alveolar concentration (iMAC). The iMAC for each pony [mean 0.97% (SD 0.17%)] was determined in a previous study.13
The skin over the right jugular vein and the left carotid artery was clipped and surgically prepared for percutaneous placement of intravascular catheters. The right jugular vein was catheterized with a 13-gauge catheter (Intranule PP, Vygon, Ecouen, France), and Ringer's lactate solution 10 ml kg–1 h–1 (RLS, Laboratorium Bichsel Baar, Switzerland) was delivered intravenously throughout the procedure with the aid of two volumetric infusion pumps (Vet/IV 2.2 Heska, Ballerup, Denmark). The left carotid artery was catheterized using a 20G/1.10 x 45 mm arterial catheter (B-D Arterial Cannula with FloSwitch, Ohmeda, Swindon, UK). Later on, the jugular port served for test drug administration and the arterial port served for blood sampling and invasive blood pressure monitoring. To facilitate test drug administration or blood collection, three-way stopcock valves were attached to the hubs of the venous and arterial catheters between the RLS line and the invasive blood pressure line, respectively.
Anaesthesia monitoring and physiological data collection
A lead II electrocardiogram was displayed and haemoglobin oxygen saturation (SpO2) was determined with a pulse oximeter infrared probe placed on the tongue, which also calculated the pulse rate (PR). Inspired and expired O2 concentrations, end-expired isoflurane concentrations (FE' ISO), capnogram and end-tidal carbon dioxide partial pressure (PE'CO2), tidal volume (VT), and minute volume ventilation (VE) were obtained from a calibrated pitot tube flow sensor and side-stream gas sampler probe (D-lite Patient Spirometry TM, Datex-Ohmeda, Helsinki, Finland) inserted between the endotracheal tube and the Y-piece of the breathing system. Respiratory rate (Rf) was calculated from the capnogram. Mean arterial pressure (MAP) was determined directly with a calibrated pressure transducer (Angiokard, Medizintechnik GmbH & Co. KG, Friedeburg, Germany) from the catheter placed in the carotid artery. The zero level in the transducer was set at the presumed level of the heart base (point of shoulder). In addition, the difference of the pharyngeo-oesophageal temperature (
T°) between the initial value measured after endotracheal intubation and the final value measured at the end of the procedures was recorded. A portable anaesthesia monitor (Datex S-5 portable anaesthesia monitor, Datex-Ohmeda, Helsinki, Finland) continuously displayed the aforementioned data. The monitor was calibrated with a standardized calibration gas (DOT-34 NRC/375M1014, Datex-Ohmeda, Helsinki, Finland) prior to each experiment according to the manufacturers' instructions. A laptop computer connected to the monitor served to record every 5 min the displayed data from 5 min before the test drug administration (baseline data) and throughout the sampling time. In addition, the need for IPPV was also manually recorded. After complete recovery from anaesthesia, animals were returned to their boxes.
Drug administration and sample collection
Ponies were left to stabilize end-tidal isoflurane concentrations to their individual isoflurane MAC for about 20 min. A single i.v. dose of R-/S-ketamine (RS-k) 2.2 mg kg–1 or S-ketamine (S-k) 1.1 mg kg–1 were administered intravenously. Five millilitres of arterial blood were collected manually over 5 s into heparinized tubes from the carotid artery catheter immediately before and at 1, 2, 4, 8, 16, 32, 64, 128 min after test drug injection. To avoid contamination with the arterial flushing solution, 5 ml of blood was collected and discharged before every sampling event. After the samples were obtained, the arterial catheter was flushed with 10 ml of physiologic saline solution. Immediately after collection, the samples were placed on ice until centrifugation was performed (maximum: 45 min) and plasma was frozen at – 80°C until the assay was performed.
Ketamine and norketamine enantiomer analysis
The plasma samples were analysed by enantioselective capillary electrophoresis (CE) according to the technique described by Theurillat and colleagues,14 and plasma concentrations for R-ketamine, S-ketamine, R-norketamine, and S-norketamine were obtained. Briefly, this technique is based on liquid–liquid extraction of ketamine and norketamine at alkaline pH from 1 ml plasma followed by analysis of the reconstituted extract by CE in the presence of a pH 2.5 Tris–phosphate buffer containing highly sulfated ß-cyclodextrin 10 mg ml–1 (Sigma Aldrich Chemie, Schnelldorf, Germany) as chiral selector. Analyses were performed on the P/ACE MDQ Capillary Electrophoresis Analyzer (Beckman Coulter, Fullerton, CA, USA) using a 50 µm ID fused-silica capillary of 28 cm effective length, an applied voltage of – 20 kV and a cartridge temperature of 30°C. The detection wavelength was 195 nm. The limit of detection for all enantiomers was 0.01 µg ml–1 and intraday and interday precisions (n = 5) were < 8% and < 14%, respectively.
Pharmacokinetic analysis
R-ketamine and S-ketamine concentration vs time curves were analysed for each individual by non-linear least square regression two-compartment model analysis using PCNonlin (SCI Software, Lexington, USA). Plasma concentration obtained after i.v. administration was fitted to a polyexponential equation:
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i (per hour) is its exponent. Initial estimates were determined using the residual method15 and refitted by non-linear regression analysis. The number of exponents needed were determined by applying the Schwartz16 and Akaike criteria.17 Most pharmacokinetic parameters were calculated using classic equations associated with compartmental analysis. Distribution and elimination half-lives (t1/2alpha and t1/2beta, respectively) were calculated as t1/2alpha = 0.693/1 and t1/2beta = 0.693/2. Area under the plasma concentration–time curve (AUC(0–
)) and mean residence time (MRT, measure of drug elimination expressed as the average time a drug molecule remains in the body after i.v. injection) were calculated by the trapezoidal rule with extrapolation to infinity. The extrapolated area was estimated as AUC(Clast–) = Clast/2, where Clast is the last measured concentration. Body clearance (ClB) was determined as ClB = dose/AUC(0–) and the steady-state volume of distribution (V(d(ss))) was calculated as V(d(ss)) = ClB x MRT. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, Cmax, and Tmax.
Statistical methods
The NCSS 2004 (Kaysville, UT, USA) and the SigmaStat 3.1 (Point Richmond, CA, USA) software packages were used to perform the statistical evaluation. All data were analysed for normal distribution with the Martinez–Iglewicz test. The significance of difference between groups for T°, ketamine, and norketamine enantiomers plasma levels and the estimated pharmacokinetic parameters was assessed with the Wilcoxon signed rank test or, when applicable, the Student's paired t-test. Each animal served as its own match. For PR, MAP, PE'CO2, Rf, and VE, a statistical comparison was made between SR-k and S-k treatment groups before and after test drug administration using an analysis of variance test and for VT using a two-way analysis on ranks Friedman test. For all tests, overall P < 0.05 was considered the minimum level of statistical significance. Parametric data are presented as mean (SD) and non-parametric data are presented as median and range.
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Anaesthesia
The overall induction, maintenance, and recovery from the anaesthetic episodes were uneventful. In one pony, the administration of the S-ketamine and the RLS infusions were performed via a 16-gauge catheter placed in the right cephalic vein because of obstruction of the left jugular vein catheter. Differences between treatment groups in
T° were not statistically significant [RS-k: 0.6 (0.4)°C; S-k: 0.9 (0.6)°C].
Cardiopulmonary data
There were no statistically significant differences in the cardiopulmonary variables between groups during the baseline measurements. Trends for PR are presented in Figure 1. Ponies in the RS-k treatment group had significantly lower (P < 0.001) overall PR compared with the S-k treatment group (Fig. 1). Trends for MAP are presented in Figure 2. Overall MAP values where higher (P = 0.006) in the RS-k when compared with the S-k group. Trends for PE'CO2, VE, and Rf are presented in Figure 3. Ponies in the S-k treatment group had a significantly lower (P < 0.001) PE' CO2 compared with the RS-k treatment group (Fig. 3A). The VE was significantly higher (P < 0.001) in the RS-k treatment group than in the S-k treatment group (Fig. 3B). Overall Rf values were higher (P < 0.001) in the RS-k treatment group than the S-k treatment group (Fig. 3C). Immediately after both test drug administrations, three of seven ponies in each group developed apnoea longer than 30 s. After applying IPPV for 1–2 min all of them restored to spontaneous respiration. Differences in VT were not statistically significant between treatment groups (RS-k group, median: 1.04 litre, range: 0.24–2.61 litre; S-k group, median: 0.99 litre, range: 0.05–3.06 litre). VT decreased in both groups after test drug administration and restored to baseline values at 10 min. Mean SpO2 for the entire anaesthetic episode was 99 (0.9)% in the RS-k treatment group and 98.8 (0.4)% in the S-k treatment group.
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Plasma concentrations of ketamine and norketamine enantiomers
A total of 126 plasma samples (RS-k = 63, S-k = 63) were analysed by CE and used for the concentration–time data evaluation. R-ketamine and R-norketamine were not detected after administration of S-ketamine. Trends for ketamine and norketamine plasma concentrations are presented in Figures 4 and 5. S-ketamine plasma concentrations were statistically significantly lower (P = 0.03) in the S-k treatment group than in the RS-k treatment group at 2 min (Figs 4A and 5A). At the same time point, S-ketamine plasma concentrations were statistically significantly lower (P = 0.005) when compared with the R-ketamine plasma concentrations in the RS-k treatment group (Fig. 4A). No other significant differences were determined. Plasma concentrations for S-norketamine were statistically significantly higher than plasma concentrations of R-norketamine in the RS-k group at 2 (P = 0.005), 8 (P = 0.007), 16 (P = 0.01), 32 (P = 0.005), 64 (P = 0.008), and 128 (P = 0.03) min. No statistical difference was noted at 1 (P = 0.297) and 4 (P = 0.147) min. The plasma concentrations of the S-norketamine in the S-k group were similar to its homologous enantiomer in the RS-k group (P > 0.05 for all time points, Figs 4B and 5B).
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Pharmacokinetic analysis
The pharmacokinetics for all ketamine enantiomers could be well described with a two-compartment model. No significant differences in the pharmacokinetic variables between and within treatment groups could be detected for the ketamine enantiomers. The AUC and Cmax of R-norketamine were found to be significantly smaller (P = 0.002 and P = 0.009, respectively) than those of S-norketamine in the RS-k treatment group. No other significant differences could be determined. Table 1 summarizes the results of the population analysis for all compounds.
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In the present study, the pharmacokinetic parameters of R- and S-ketamine after single i.v. injection of the racemate or the single S-enantiomer in ponies under isoflurane anaesthesia, did not significantly differ. The statistically significant differences found for the S-ketamine plasma concentrations 2 min after administration of either R-/S- or S-ketamine had no significant impact on the calculated pharmacokinetic variables. However, the statistically significant differences found in the plasma disposition of S- and R-norketamine after administration of the racemate, mirrored by their calculated pharmacokinetic parameters, suggest that in ponies anaesthetized with 1 iMAC isoflurane, the metabolism of racemic ketamine is highly stereoselective. In both treatment groups, the arterial plasma concentrations of ketamine enantiomers followed a biexponential decline, with a rapid initial distribution phase being followed by a slower elimination phase. This profile was analogous to those previously published for humans,11 dogs,18 and cross-bred horses.5 Similar to humans and most other species,1 2 4 5 10 18–21 high variability among individuals was observed in the plasma concentrations of ketamine and norketamine. Former studies on the pharmacokinetics of S-/R-ketamine in horses reported data analysed from venous samples.1–5 In isoflurane anaesthetized ponies, large differences (up to 50%) were found between arterial and venous pharmacokinetics of ketamine isomers caused by both, distribution and elimination processes.22 In situations in which potent short-acting drugs are used, such as anaesthetics, these differences can be of considerable importance.23 Because the drug concentrations at the target organ are probably more closely related to arterial than to venous concentration, the controlling parameters should be based on arterial rather than venous data.10 24 The present study is the first investigating the arterial stereoselective pharmacokinetic profile of S-/R-ketamine compared with S-ketamine in an equine species.
The iMAC is the midpoint of two end-tidal anaesthetic concentrations that just permit or just prevent gross purposeful movement after applying a supramaximal stimulation in a single anaesthetized individual.25 Individual MAC values are normally averaged to obtain the MAC in a group of subjects. The use of each pony iMAC, instead of the MAC of the group, aimed to have a comparable degree of immobility among test animals. I.V. R-/S-ketamine at a dose of 2.2 mg kg–1 is well documented to induce anaesthesia in sedated horses.2 4 Such doses, however, are seldom administered in clinical practice to horses already receiving 1 MAC of isoflurane. This dose was chosen deliberately to create a basis for further studies on constant rate infusion of ketamine in isoflurane-anaesthetized horses. As a racemate has equal proportions of each enantiomer, a dose of 1.1 mg kg–1 of S-ketamine was chosen to compare the profiles of the S-enantiomer in both treatment groups.
Previous investigations in rats21 and dogs26 anaesthetized with halogenated agents showed alterations in organ perfusion, which in turn slowed down uptake, distribution, and redistribution of ketamine. Thus, an increased apparent volume of the central compartment (Vc) could be expected, probably because of a slower elimination of the compounds by poorly perfused organs of elimination. It has long been suggested that distribution of drugs may be not only affected by blood flow but also by active transport across the endothelium.27 It was postulated that the binding affinity of the chiral forms of ketamine to membrane receptors responsible for protein-mediated transport across the vascular endothelium might exhibit stereospecificity, showing different distribution profiles between enantiomers. However, several authors failed to demonstrate ketamine distribution to be stereoselective in humans10 11 28 and in dogs.18 Similarly, in the present study, the half-lives and the Vc for the ketamine enantiomers did not differ significantly between and within groups, suggesting that ketamine distribution is not enantioselective in the equine species either.
MRT and ClB values calculated from the arterial plasma ketamine concentrations determined after S-ketamine or R-/S-ketamine i.v. administration were similar for all enantiomers. Studies conducted in humans showed a significantly higher ClB for S-ketamine compared with R-ketamine after administration of either enantiomer.11 28 29 Ihmsen and colleagues10 showed a higher S-ketamine body clearance in men when the drug was administered as an infusion of the pure enantiomer compared with an infusion of the racemate. In contrast, Yanagihara and colleagues30 showed no differences between the pharmacokinetics of ketamine enantiomers and this dissimilarity was attributed to variability related to human races. Inter-individual variations between comparison groups, differences in the sampling site (arterial vs venous), or both might also account for such discrepancies.10
Several factors seem to have an important impact on the metabolism of the ketamine isoforms. Ketamine is rapidly and extensively metabolized by the hepatic microsomal cytochrome P450 enzymes to norketamine, hydroxynorketamine, hydroxyketamine, and dehydronorketamine.31–35 In vitro studies revealed that N-demethylation of S-ketamine by human liver microsomes is 20% larger than that of R-ketamine and 10% greater when compared with the racemic compound.36 Two enzymes with stereospecific preference for one enantiomer over the other, or four enzymes with different stereospecific substrate activities and different metabolic rates might account for this enantioselective N-demethylation.36 In contrast another in vitro study with human liver microsomes suggested a non-enantioselective N-demethylation of R- and S-ketamine.37
The comparable values obtained for the calculated pharmacokinetic variables of the S-isoforms of ketamine and norketamine in both groups suggest no interference of the R-enantiomer with the overall elimination of the S-enantiomer in the racemate. However, the significant differences found for the R- and S-norketamine in the RS-k treatment group suggest that some differences exist with regard to their particular metabolic pathways. This finding corresponds with data in which similar results were obtained after a single dose of S- or R-/S-ketamine administration to human patients11 and horses.5 In the latter study, a S/R ratio for norketamine of 75:25 immediately after and 90:10 40 min after i.v. administration of R-/S-ketamine (6 mg kg–1) was reported. The authors postulated that these ratios could be the consequence of substrate enantioselectivity of the cytochrome-dependent N-demethylation. In the present study, an enzyme–substrate competition seems unlikely because similar ClB rates were found for the S-enantiomer in both groups suggesting the presence of other enantioselective processes involved in the elimination of ketamine. Norketamine is a pharmacologically active metabolite and was found to have a potency of around 30% of that of the parent drug.38 The hydroxylated metabolite 6-hydroxynorketamine has been reported to be a weaker anaesthetic and to produce less post-anaesthetic excitation than norketamine.39 Consequently, norketamine elimination pathways might have a relevant influence on the overall ketamine activity. Interestingly, the hydroxylation of norketamine also exhibited enantioselectivity at different positions on the cyclohexanone ring.35 Therefore, it could be possible that in the present study, R-norketamine hydroxylation may have prevailed, accounting for the lower plasma concentrations reflected into the lower AUC and Cmax observed for that metabolite. Unfortunately, we were unable to quantify the plasma concentrations of the hydroxylated forms of norketamine to test this hypothesis.
Renal excretion seems to play a significant role in norketamine elimination in horses.40 Differences in plasma protein binding leading to different renal clearance may be expected for chiral compounds.41 Therefore, different renal clearance rates for norketamine enantiomers could also explain the higher concentrations obtained for S-norketamine in ponies' plasma when compared with those of R-norketamine. Kaka and colleagues4 proposed involvement of extrahepatic pathways in the ketamine metabolism in horses because the ketamine ClB exceeded the calculated hepatic plasma flow rate. Studies performed in rats reported extrahepatic inversion of R to S-ketamine with subsequent metabolism to S-norketamine.42 In the present study, no R-ketamine was detected after administration of the pure S-enantiomer, and after administration of the racemate, the mean plasma concentrations of R- and S-ketamine were similar, suggesting no inversion between the R- and S-enantiomers. Geisslinger and colleagues11 proposed that a possible inversion from R- to S-ketamine could be masked by different stereoselective ClB rates, resulting also in similar concentration profiles for both enantiomers. However, the ClB of the R- and S-ketamine were similar in our study.
Although the study reported here was mainly designed to evaluate the pharmacokinetics of ketamine and norketamine enantiomers, some cardiopulmonary data were also collected. Generally, low doses of R-/S-ketamine are known to increase heart rate and MAP as a consequence of direct sympathetic stimulation.43 The reduction in MAP observed for both compounds in the first 10 min after drug administration could have been the result of direct central nervous system depression in response to the high doses used here. S-ketamine seemed to have produced a stronger cardiac stimulation as evaluated by higher PR values observed for the S-k group compared with the RS-k group. In vitro studies showed an inhibition of the uptake of noradrenaline at adrenergic neuronal endings by ketamine, which occurred pre-synaptically with both enantiomers but also post-synaptically with the S-isoform.44 On the other hand, overall mean MAP values remained significantly lower over time in the S-k treatment group compared with the racemate. The reduced MAP values observed in the S-k treatment group could have induced an autonomic reflex response that increased the heart rate and vice versa for the RS-k treatment group. Contrary to these findings, Filzek and colleagues45 reported significantly lower heart rate and higher MAP values in horses anaesthetized with S-ketamine compared with those receiving R-/S-ketamine. In man, several studies compared R-/S-ketamine with S-ketamine and found equivalent cardiovascular stimulation.10 46 47 Immediately after test drug administration and for about 10 min, respiratory depression occurred (apnoea, decreases in Rf, VT, and VE). A progressive increase in VE was observed in both groups as test drugs were cleared from plasma. Increases in Rf might have accounted for the overall increases in the mean VE values observed in the RS-k treatment group since VT remained similar between groups. In turn, an overall increase in the arterial partial pressure of carbon dioxide, reflected as an increase in the overall mean PE'CO2 values in the RS-k treatment group, could have stimulated the respiratory system via chemoreceptor activity resulting in the observed increases in VE and Rf. Alternatively, increases in physiologic dead space could explain the lower PE'CO2 values observed in the S-k treatment group.
In conclusion, the disposition of racemic ketamine in ponies anaesthetized with 1 iMAC isoflurane is stereoselective, leading to higher plasma concentrations of S-norketamine. Several factors seem to influence the metabolism of the ketamine isoforms. Further studies are required to assess the impact of different dose regimes, drug combinations, or both on the overall metabolism of the enantiomers of ketamine. Under the conditions reported here, administration of S-ketamine produced different cardiopulmonary effects than those observed with R-/S-ketamine. The underlying mechanisms responsible for these differences remain to be elucidated.
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The study was supported by grants from the Vetsuisse Faculty of the University of Bern, Bern, Switzerland, the Swiss National Science Foundation and Dr E. Gräub Laboratories.
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1 Taylor PM, Luna SP, Sear JW, Wheeler MJ. (1995) Total intravenous anaesthesia in ponies using detomidine, ketamine and guaiphenesin: pharmacokinetics, cardiopulmonary and endocrine effects. Res Vet Sci 59:17–23.[CrossRef][Web of Science][Medline]
2 Waterman AE, Robertson SA, Lane JG. (1987) Pharmacokinetics of intravenously administered ketamine in the horse. Res Vet Sci 42:162–6.[Web of Science][Medline]
3 Nolan A, Reid J, Welsh E, Flaherty D, McCormack R, Monteiro AM. (1996) Simultaneous infusions of propofol and ketamine in ponies premedicated with detomidine: a pharmacokinetic study. Res Vet Sci 60:262–6.[CrossRef][Web of Science][Medline]
4 Kaka JS, Klavano PA, Hayton WL. (1979) Pharmacokinetics of ketamine in the horse. Am J Vet Res 40:978–81.[Web of Science][Medline]
5 Delatour P, Jaussaud P, Courtot D, Fau D. (1991) Enantioselective N-demethylation of ketamine in the horse. J Vet Pharmacol Ther 14:209–12.[Web of Science][Medline]
6 Ariens EJ. (1986) Stereochemistry: a source of problems in medicinal chemistry. Med Res Rev 6:451–66.[CrossRef][Web of Science][Medline]
7 Kohrs R and Durieux ME. (1998) Ketamine: teaching an old drug new tricks. Anesth Analg 87:1186–93.
8 Ryder S, Way WL, Trevor AJ. (1978) Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol 49:15–23.[CrossRef][Web of Science][Medline]
9 White PF, Schuttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ. (1985) Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth 57:197–203.
10 Ihmsen H, Geisslinger G, Schuttler J. (2001) Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine. Clin Pharmacol Ther 70:431–8.[Web of Science][Medline]
11 Geisslinger G, Hering W, Thomann P, Knoll R, Kamp HD, Brune K. (1993) Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br J Anaesth 70:666–71.
12 Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P. (1992) Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings. Anaesthesist 41:610–8.[Web of Science][Medline]
13 Spadavecchia C, Levionnois O, Kronen PW, Leandri M, Spadavecchia L, Spadavecchia U. (2006) Evaluation of administration of isoflurane at approximately the minimum alveolar concentration on depression of a nociceptive withdrawal reflex evoked by transcutaneous electrical stimulation in ponies. Am J Vet Res 67:762–9.[CrossRef][Web of Science][Medline]
14 Theurillat R, Knobloch M, Levionnois O, Larenza P, Mevissen M, Thormann W. (2005) Characterization of the stereoselective biotransformation of ketamine to norketamine via determination of their enantiomers in equine plasma by capillary electrophoresis. Electrophoresis 26:3942–51.[CrossRef][Web of Science][Medline]
15 Gibaldi M and Perrier D. (1982) Pharmacokinetics 2 (Marcel Dekker Inc, New York, USA) pp. 433–44.
16 Schwartz G. (1978) Estimating the dimension of a model. Ann Stat 6:461–4.[CrossRef]
17 Yamaoka K, Nakagawa T, Uno T. (1978) Application of Akaikés information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 6:165–75.[CrossRef][Web of Science][Medline]
18 Henthorn TK, Krejcie TC, Niemann CU, Enders-Klein C, Shanks CA, Avram MJ. (1999) Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective. Anesthesiology 91:1733–43.[CrossRef][Web of Science][Medline]
19 Freye E, Latasch L, Schmidhammer H. (1992) Pharmacodynamic effects of S-(+)-ketamine on EEG, evoked potentials and respiration. A study in the awake dog. Anaesthesist 41:527–33.[Web of Science][Medline]
20 Hanna RM, Borchard RE, Schmidt SL. (1988) Pharmacokinetics of ketamine HCl and metabolite I in the cat: a comparison of i.v, i.m, and rectal administration. J Vet Pharmacol Ther 11:84–93.[Web of Science][Medline]
21 White PF, Marietta MP, Pudwill CR, Way WL, Trevor AJ. (1976) Effects of halothane anesthesia on the biodisposition of ketamine in rats. J Pharmacol Exp Ther 196:545–55.
22 Larenza MP, Landoni MF, Knobloch M, Levionnois OL, Kronen PW, Theurillat R, et al. Impact of sampling site on the disposition of S-ketamine and R-ketamine after single intravenous administration of the racemic mixture in Shetland ponies under isoflurane anaesthesia Association of Veterinary Anaesthetists, Spring Meeting, 20–23 April, 2005, Rimini, Italy, 81.
23 Chiou WL. (1989) The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I). Clin Pharmacokinet 17:175–99.[Web of Science][Medline]
24 Chiou WL, Lam G, Chen ML, Lee MG. (1981) Arterial-venous plasma concentration differences of six drugs in the dog and rabbit after intravenous administration. Res Commun Chem Pathol Pharmacol 32:27–39.[Web of Science][Medline]
25 Jinks SL, Martin JT, Carstens E, Jung SW, Antognini JF. (2003) Peri-MAC depression of a nociceptive withdrawal reflex is accompanied by reduced dorsal horn activity with halothane but not isoflurane. Anesthesiology 98:1128–38.[CrossRef][Web of Science][Medline]
26 Schwieger IM, Szlam F, Hug CC Jr. (1991) The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokinet Biopharm 19:145–56.[CrossRef][Web of Science][Medline]
27 Renkin EM and Curry FE. (1982) Endothelial permeability: pathways and modulations. Ann NY Acad Sci 401:248–59.[Web of Science][Medline]
28 Persson J, Hasselstrom J, Maurset A, Oye I, Svensson JO, Almqvist O, et al. (2002) Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol 57:869–75.[CrossRef][Web of Science][Medline]
29 White PF, Ham J, Way WL, Trevor AJ. (1980) Pharmacology of ketamine isomers in surgical patients. Anesthesiology 52:231–9.[CrossRef][Web of Science][Medline]
30 Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, et al. (2003) Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos 24:37–43.[CrossRef][Web of Science][Medline]
31 Hijazi Y and Boulieu R. (2002) Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 30:853–8.
32 Chang T and Glazko AJ. (1974) Biotransformation and disposition of ketamine. Int Anesthesiol Clin 12:157–77.[Medline]
33 Woolf TF and Adams JD. (1987) Biotransformation of ketamine, (Z)-6-hydroxyketamine, and (E)-6-hydroxyketamine by rat, rabbit, and human liver microsomal preparations. Xenobiotica 17:839–47.[Web of Science][Medline]
34 Leung L and Baillie T. (1986) Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J Med Chem 29:2396–9.[CrossRef][Web of Science][Medline]
35 Adams JD Jr, Baillie TA, Trevor AJ, Castagnoli N Jr. (1981) Studies on the biotransformation of ketamine. 1—Identification of metabolites produced in vitro from rat liver microsomal preparations. Biomed Mass Spectrom 8:527–38.[CrossRef][Web of Science][Medline]
36 Kharasch ED and Labroo R. (1992) Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology 77:1201–7.[CrossRef][Web of Science][Medline]
37 Yanagihara Y, Kariya S, Ohtani M, Uchino K, Aoyama T, Yamamura Y, et al. (2001) Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 29:887–90.
38 Sear JW. (1991) Continuos infusion of hypnotic agents for maintenance of anaesthesia. In Kay B (Ed.). Total Intravenous Anaesthesia 1st Edn (Elsevier Science, Amsterdam) pp. 38–40.
39 Hong SC and Davisson JN. (1982) Stereochemical studies of demethylated ketamine enantiomers. J Pharm Sci 71:912–4.[CrossRef][Web of Science][Medline]
40 Sams R and Pizzo P. (1987) Detection and identification of ketamine and its metabolites in horse urine. J Anal Toxicol 11:58–62.[Web of Science][Medline]
41 Delatour P, Benoit E, Garnier F, Besse S. (1990) Chirality of the sulphoxide metabolites of fenbendazole and albendazole in sheep. J Vet Pharmacol Ther 13:361–6.[Web of Science][Medline]
42 Edwards SR and Mather LE. (2001) Tissue uptake of ketamine and norketamine enantiomers in the rat: indirect evidence for extrahepatic metabolic inversion. Life Sci 69:2051–66.[CrossRef][Web of Science][Medline]
43 Hill GE, Wong KC, Shaw CL, Sentker CR, Blatnick RA. (1978) Interactions of ketamine with vasoactive amines at normothermia and hypothermia in the isolated rabbit heart. Anesthesiology 48:315–9.[CrossRef][Web of Science][Medline]
44 Martin DC, Watkins CA, Adams RJ, Nason LA. (1988) Anesthetic effects on 5-hydroxytryptamine uptake by rat brain synaptosomes. Brain Res 455:360–5.[CrossRef][Web of Science][Medline]
45 Filzek U, Fischer U, Ferguson J. (2003) Intravenous anaesthesia in horses: racemic ketamine versus S-(+)-ketamine. Pferdeheilkunde 19:501–6.
46 Doenicke A, Angster R, Mayer M, Adams HA, Grillenberger G, Nebauer AE. (1992) The action of S-(+)-ketamine on serum catecholamine and cortisol. A comparison with ketamine racemate. Anaesthesist 41:597–603.[Web of Science][Medline]
47 Adams HA, Thiel A, Jung A, Fengler G, Hempelmann G. (1992) Studies using S-(+)-ketamine on probands. Endocrine and circulatory reactions, recovery and dream experiences. Anaesthesist 41:588–96.[Web of Science][Medline]
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