Fast and reliable analysis of veterinary metomidate and etomidate in human blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a postmortem case.

Metomidate and etomidate belong to the non-barbiturate imidazole family of sedative-hypnotics and elicit little analgesic action when used alone. Metomidate, in particular, has little analgesic activity in humans and is, therefore, used for veterinary purposes. In 2019, a Korean woman in her twenties was found unconscious in a motel bath and eventually died. Etomidate, alprazolam, escitalopram, and metomidate were detected in the postmortem specimens. To our knowledge, this is the first case of human metomidate abuse reported in the Republic of Korea. In this research, a simple and reliable method was developed for the analysis of metomidate and etomidate in human blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Blood samples were deproteinized with acetonitrile, filtered, and analyzed by LC-MS/MS. Linear calibration curves were obtained with six concentrations ranging from 1 to 50 ng/ml for metomidate and 10 to 500 ng/ml for etomidate. The method was validated by assessing the selectivity, linearity, limit of detection (LOD), limit of quantitation (LOQ), intra- and inter-day precision and accuracy, matrix effect, and stability and successfully applied to the analysis of metomidate and etomidate in human blood samples. In a postmortem case, the concentrations of metomidate and etomidate were found to be 8 and 110 ng/ml in femoral blood and 6 and 210 ng/ml in cardiac blood, respectively.

Application of petal-shaped ionic liquids modified covalent organic frameworks for one step cleanup and extraction of general anesthetics in human plasma samples.

Here, the novel petal-shaped ionic liquids modified covalent organic frameworks (PS-IL-COFs) particles have been synthesized by using ionic liquids as modifying agent, which could be beneficial to avoid the aggregation of COFs during the preparation and improve its dispersing performance. The novel PS-IL-COFs particles have been used and evaluated in the one step cleanup and extraction (OSCE) procedure for human plasma prior to the analysis of 3 general anesthetics by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). In the OSCE procedure, human plasma samples are directly mixed with extraction solvent and PS-IL-COFs particles, and the extraction and cleanup procedure have been carried out simultaneously. Compared with the Oasis PRiME HLB cartridge method, the OSCE procedure using PS-IL-COFs particles as sorbents is much more effective for the minimization of ion suppression resulted from blood phospholipids. Under optimal conditions, the PS-IL-COFs particles show higher cleanup efficiency of 3 general anesthetics with recoveries in the range of 82.5%-115%. The limits of quantification (LOQs) for propofol, ketamine and etomidate are 0.18 µg/L, 0.15 µg/L and 0.016 µg/L, respectively. Validation results on linearity, specificity, precision and trueness, as well as on the application to analysis of general anesthetics in a case of a 54-year-old female suffered gallstone demonstrate the applicability to clinical studies.

Preclinical Pharmacokinetics Study of a Novel Intravenous Anesthetic ET-26 Hydrochloride.

BACKGROUND: ET-26 hydrochloride is a novel intravenous anesthetic, approved for clinical trials, that produces a desirable sedative-hypnotic effect with stable myocardial performance and mild adrenocortical suppression in rats and beagle dogs. The objective of this study was to assess the absorption, distribution, metabolism, and excretion of ET-26 hydrochloride. METHODS: Hepatocytes from human, monkey, dog, rat, and mouse were used to determine the metabolites of ET-26 hydrochloride. Distribution and excretion were assessed in rats and pharmacokinetic studies were performed in beagle dogs. RESULTS: The metabolic pathway and proposed structure of metabolites were fully assessed resulting from the biotransformation reactions of hydrolysis, dehydrogenation, demethylation and glucuronic acid conjugation. The main distribution of the drug was in fat (15067 ± 801 ng/ml) and liver (13647 ± 1126 ng/ml), and the kidney was the primary excretion route (4.47%-11.94%). The Cmax after injection with 1.045 mg/kg, 2.09 mg/kg, and 4.18 mg/kg was 1476.5 ± 138.9 ng/ml, 2846.1 ± 223.3 ng/ml, and 6233.3 ± 238.9 ng/ml, respectively. The t1/2 of the drug was similar across dose groups at 74.8 ± 10.8 min to 81.4 ± 4.2 min. The AUC0-t values were 30208.1 ± 2026.5 min*ng/ml, 62712.8 ± 1808.3 min*ng/ml, and 130465.2 ± 7457.4 min*ng/ml, respectively. CONCLUSION: The metabolic pathway and the proposed structure of metabolites for ET-26 hydrochloride were fully assessed. The majority of distribution for ET-26 hydrochloride occurs in the fat and liver, while the primary route of excretion for ET-26 hydrochloride is through the kidney. In dogs, pharmacokinetic features of ET-26 hydrochloride had a linear relationship with dosage.

Ketamine and Etomidate Down-regulate the Hypothalamic-Pituitary-Adrenal Axis in an Endotoxemic Mouse Model.

BACKGROUND: We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis. METHODS: Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3ß-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11ß-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD). RESULTS: At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P < 0.01), proopiomelanocortin (21 ± 3 vs. 8 ± 0.9, P < 0.0001), P450 side-chain cleavage (32 ± 4 vs. 23 ± 10, P < 0.05), 21-hydroxylase (17 ± 5 vs. 12 ± 2, P < 0.05), and 11ß-hydroxylase (11 ± 4 vs. 6 ± 0.5, P = 0.001), and an elevation of corticosterone (642 ± 165 vs. 98.3 ± 63 ng/ml, P < 0.0001). Etomidate and ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P < 0.01), 21-hydroxylase (8 ± 0.8 and 8 ± 1 vs. 17 ± 5, P < 0.001), 11ß-hydroxylase (4 ± 0.5 and 7 ± 1 vs. 11 ± 4, P < 0.001 and P < 0.05), and corticosterone (413 ± 189 and 260 ± 161 vs. 642 ± 165 ng/ml, P < 0.05 and P < 0.01). Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P < 0.05). At 48 h, all four adrenal enzymes were down-regulated by lipopolysaccharide administration with corticosterone levels similar to the control group. Ketamine and etomidate did not modify corticosterone plasma levels. CONCLUSIONS: Our endotoxemic model induces an initial activation of the hypothalamic-pituitary-adrenal axis, followed by a secondary inhibition of adrenal steroidogenesis processes. Ketamine and etomidate inhibit the enzyme expression and activity of the adrenal gland at the early stage.

Unrepaired Tetralogy of Fallot-related Pathophysiologic Changes Reduce Systemic Clearance of Etomidate in Children.

BACKGROUND: Pathophysiologic changes in children with congenital heart disease may alter the effect of drugs by influencing the pharmacokinetics (PK). Considering the limited literature that describes the PK of etomidate in pediatric patients, especially in those with tetralogy of Fallot (TOF), our aim was to characterize the PK of etomidate and explore the effects of TOF. METHODS: Twenty-nine pediatric patients (15 with TOF and 14 with normal cardiac anatomy) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received etomidate 60 µg/kg/min intravenously until a bispectral index of ≤50 was reached for 5 seconds during anesthesia induction. Arterial blood samples were drawn and analyzed. Population analysis was performed by using NONMEM to define PK characteristics. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: Data consisting of 244 samples from 29 children with a mean age of 236 days (range, 86-360 days) were used, including a TOF group with a mean age of 250 days (range, 165-360 days) and a normal cardiac anatomy group with a mean age of 221 days (range, 86-360 days). A 3-compartment disposition model was best fitted to describe the PK of etomidate. The introduction of TOF as a covariate for systemic clearance (Cl1) improved the model and resulted in a significant reduction of objective function (Δobjective function = -7.33; P = .0068), which means that TOF was a significant covariate of Cl1, and the etomidate Cl1 in children with TOF (1.67 × (weight [WT]/70 kg) L/min) was lower than those with normal cardiac anatomy (2.28 × (WT/70 kg) L/min). Other PK parameter values were as follows: V1 = 8.05 × (WT/70 kg) L; V2 = 13.7 × (WT/70 kg) L; V3 = 41.3 × (WT/70 kg) L; Cl2 = 3.35 × (WT/70 kg) L/min; Cl3 = 0.563 × (WT/70 kg) L/min. CONCLUSIONS: A decreased systemic clearance for etomidate in children with TOF resulted in a lower required infusion rate and variation with time to achieve the same plasma concentration and maintain an equivalent target concentration or have longer sedation and recovery times after bolus or continuous infusion than normal children.

Effect of etomidate and propofol induction on hemodynamic and endocrine response in patients undergoing coronary artery bypass grafting/mitral valve and aortic valve replacement surgery on cardiopulmonary bypass.

INTRODUCTION: The concerns for induction of anaesthesia in patients undergoing cardiac surgery include hemodynamic stability, attenuation of stress response and maintenance of balance between myocardial oxygen demand and supply. Various Intravenous anaesthetic agents like Thiopentone, Etomidate, Propofol, Midazolam, and Ketamine have been used for anesthetizing patients for cardiac surgeries. However, many authors have expressed concerns regarding induction with thiopentone, midazolam and ketamine. Hence, Propofol and Etomidate are preferred for induction in these patients. However, these two drugs have different characteristics. Etomidate is preferred for patients with poor left ventricular (LV) function as it provides stable cardiovascular profile. But there are concerns about reduction in adrenal suppression and serum cortisol levels. Propofol, on the other hand may cause a reduction in systemic vascular resistance and subsequent hypotension. Thus, this study was conducted to compare induction with these two agents in cardiac surgeries. METHODS: Baseline categorical and continuous variables were compared using Fisher's exact test and student's t test respectively. Hemodynamic variables were compared using student's t test for independent samples. The primary outcome (serum cortisol and blood sugar) of the study was compared using Wilcoxon Rank Sum test. The P value less than 0.05 was considered significant. RESULTS: Etomidate provides more stable hemodynamic parameters as compared to Propofol. Propofol causes vasodilation and may result in drop of systematic BP. Etomidate can therefore be safely used for induction in patients with good LV function for CABG/MVR/AVR on CPB without serious cortisol suppression lasting more than twenty-four hours.

Haematological effects of 2-phenoxyethanol and etomidate in carp (Cyprinus carpio L.).

OBJECTIVE: To evaluate the effects of handling alone versus handling under anaesthesia with 2-phenoxyethanol or etomidate on haematological parameters in carp. STUDY DESIGN: Prospective, randomized, laboratory experiment. ANIMALS: Seventy-two juvenile carp (Cyprinus carpio) weighing 35.9 ± 10.4 g were divided into six groups of 12 fish. METHODS: Either 2-phenoxyethanol or 2% etomidate were administered to induce deep anaesthesia (0.3 mL L(-1) and 0.6 mL L(-1) , respectively) or deep sedation (0.15 mL L(-1) and 0.3 mL L(-1) , respectively). Fish were handled with and without sedation. Blood was sampled at 1 hour and 1 week post-treatment. Phagocyte oxidative activity [nitrotetrazolium blue reduction test (NBT)] and differential erythrocyte [red blood cell (RBC)] and leukocyte (white blood cell) counts were evaluated. RESULTS: At 1 hour after the induction of anaesthesia, haematocrit (Ht) and haemoglobin (Hb) were increased in fish anaesthetized with 2-phenoxyethanol, and mean corpuscular haemoglobin (MCH) was increased in fish anaesthetized with etomidate. At 1 week, an increase in RBC, erythroblastosis, erythrocyte damage, lymphopenia, neutrophilia, monocytosis and thrombocytosis occurred in both groups. Red blood parameters did not change 1 hour after handling alone, but after 1 week Ht, Hb and mean cell volume decreased, whereas MCH concentration (MCHC) and abnormal erythrocytes increased. Lymphopenia, neutrophilia, monocytosis, thrombocytosis and a decrease in NBT occurred. Fish handled under sedation showed an increase in Hb and MCHC followed by a decrease at 1 week in Ht, Hb and MCH, erythroblastosis and increased abnormal erythrocytes. Lymphopenia and neutrophilia were less pronounced than in fish handled without sedation, but a decrease in NBT was noted at 1 week post-treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Deep anaesthesia with 2-phenoxyethanol or etomidate induced significant haematological alterations in juvenile carp. Deep sedation reduced the immediate immunosuppressive effects of handling but did not eliminate longterm effects. These anaesthetics should be avoided during experimental procedures involving haematological measurements. In contexts that require the short-term handling of carp, these drugs should be used with caution in view of their possible side effects.

In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.

BACKGROUND: We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11ß-hydroxylase. We hypothesized that MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of MOC-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a "soft" analog of carboetomidate. METHODS: MOC-carboetomidate's octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate's 50% effective concentration (EC(50)) and 50% effective dose for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on γ-aminobutyric acid A (GABA(A)) receptor function was assessed using 2-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. RESULTS: MOC-carboetomidate's octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15,000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate's EC(50) for LORR in tadpoles was 9 ± 1 µM and its EC(50) for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABA(A) receptor currents by 400% ± 100%. Its metabolic half-life in pooled rat blood was 1.3 min. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs 15 ± 3, respectively; P = 0.0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. CONCLUSIONS: MOC-carboetomidate is a GABA(A) receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.

Comparison of the effects of etomidate and propofol combined with remifentanil and guided by comparable BIS on transcranial electrical motor-evoked potentials during spinal surgery.

BACKGROUND: Transcranial electrical motor-evoked potentials (TceMEPs) can provide early warning of possible motor compromise during surgery. There are fewer reports comparing the effects of etomidate and propofol infusion on TceMEPs when used for the maintenance of anesthesia and guided by comparable values of bispectral index (BIS) during spinal surgery. METHODS: Thirty-three patients scheduled for spinal surgery were randomly divided into 2 groups: propofol (PR, n=18) and etomidate (ER, n=15). Anesthesia was maintained with either propofol or etomidate combined with remifentanil. The infusion rates for propofol or etomidate were guided by the BIS value, which was maintained between 40 and 45. TceMEPs were conducted by stimulating needles placed at C1 and C2; recordings were made by measuring myogenic responses from the upper extremity abductor pollicis brevis muscles using needle electrodes. The threshold for eliciting a response, amplitudes, and latencies of TceMEPs, were recorded at 30, 60, 90, and 120 minutes after the induction of anesthesia. The cortisol levels were measured at 2 and 24 hours after induction. RESULTS: The voltage threshold needed to enlist TceMEPs in the ER group was significantly lower than that in the PR group (142±20 vs. 172±23 V, P=0.005). The amplitudes of TceMEPs were higher in the ER group than those in the PR group (P<0.05), whereas the latencies were shorter in the ER group than those in the PR group (P<0.05) at all study time points. Cortisol levels at all study time points were within the normal range. CONCLUSIONS: Etomidate has more favorable effects than propofol during the monitoring of TceMEPs under comparable BIS levels.

(18)F-labelled metomidate analogues as adrenocortical imaging agents.

INTRODUCTION: Two- and one-step syntheses of (18)F-labelled analogues of metomidate, such as 2-[(18)F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[(18)F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[(18)F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[(18)F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[(18)F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. METHODS: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[(18)F]fluoroethyl 4-methylbenzenesulfonate or 3-[(18)F]fluoropropyl 4-methylbenzenesulfonate. These were used as (18)F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. RESULTS: The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46+/-3% and 79+/-30%, respectively. CONCLUSION: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG.

UNLABELLED: Our aim was to evaluate the use of PET with (11)C-metomidate and (18)F-FDG for the diagnosis of adrenal incidentalomas. METHODS: Twenty-one patients underwent hormonal screening before dynamic imaging of the upper abdomen with (11)C-metomidate, and for 19 of these 21 patients, static (18)F-FDG imaging followed. Uptake of (11)C-metomidate and (18)F-FDG in incidentalomas was quantified and correlated with the hormonal work-up and the mass size on CT (median, 2.5 cm; range, 2-10 cm). RESULTS: The final diagnoses were hormonally active adenoma (n = 7), nonsecretory adenoma (n = 5), adrenocortical carcinoma (n = 1), pheochromocytoma (n = 2), benign noncortical tumor (n = 2), normal adrenal (n = 1), and malignant noncortical tumor (n = 3). Diagnosis was established at surgery (n = 9), percutaneous biopsy (n = 4), or follow-up (n = 8). The highest uptake of (11)C-metomidate, expressed as standardized uptake value (SUV), was found in adrenocortical carcinoma (SUV = 28.0), followed by active adenomas (median SUV = 12.7), nonsecretory adenomas (median SUV = 12.2), and noncortical tumors (median SUV = 5.7). Patients with adenomas had significantly higher tumor-to-normal-adrenal (11)C-metomidate SUV ratios than did patients with noncortical tumors. (18)F-FDG detected 2 of 3 noncortical malignancies but failed to detect adrenal metastases from renal cell carcinoma. All inactive and most active adenomas were difficult to detect with (18)F-FDG against background activity, whereas both pheochromocytomas and adrenocortical carcinoma showed slightly increased uptake of (18)F-FDG. There was no correlation between uptake of (11)C-metomidate or (18)F-FDG and mass size. CONCLUSION: (11)C-Metomidate is a promising PET tracer to identify incidentalomas of adrenocortical origin. (18)F-FDG should be reserved for patients with a moderate to high likelihood of neoplastic disease.

The effects of etomidate, thiopental, and propofol in induction on hypoperfusion-reperfusion phenomenon during laparoscopic cholecystectomy.

BACKGROUND: A hypoperfusion-reperfusion human model is observed during and soon after laparoscopic surgery. The aim of the study was to research the preventive effects of etomidate, thiopental, and propofol in induction on hypoperfusion- reperfusion phenomenon during laparoscopic cholecystectomy. METHODS: Thirty-six consecutive ASA I-II patients were randomized into three groups of 12 patients each. Anaesthesia was induced with etomidate in group 1, thiopental in group 2, and propofol in group 3. Venous blood samples were obtained at different time points for measurement of plasma malondialdehyde (MDA) levels. Arterial blood and gastric juice samples were obtained for the calculation of gastric intramucosal pH (pHi). Also changes in aminotransferases, alkaline phosphatase and total bilirubin levels were assessed. RESULTS: There was a significant decrease in pHi at 1 min before desufflation (BD) and 20 min after desufflation (AD) compared with before insufflation (BI) in all groups. Plasma level of MDA was significantly increased in group 1 at 1 min BD and 20 min AD compared with before induction of anaesthesia (baseline). Malondialdehyde levels were decreased significantly in group 3 and increased non-significantly in group 2 at the same time points. Also AST and ALT levels were significantly increased in both groups 1 and 2 at 24 h postoperatively. CONCLUSION: Propofol with antioxidant activity may offer many advantages by scavenging reactive oxygen species and their metabolites in case of anticipated hypoperfusion-reperfusion phenomenon, such as would occur in laparoscopic surgery.

Pharmacokinetic and pharmacodynamic properties of metomidate in turbot (Scophthalmus maximus) and halibut (Hippoglossus hippoglossus).

Metomidate was administered to halibut (Hippoglossus hippoglossus) and turbot (Scophthalmus maximus) intravenously at a dose of 3 mg/kg bodyweight, as a bath treatment at a dose of 9 mg/L water for 5 min to study the disposition of metomidate, and as bath treatment (9 mg/L) for 10 min to study the absorption and effect of metomidate on respiration and balance/motor control. Additionally, turbot were given metomidate orally at a dose of 7 mg/kg. The studies were performed in seawater at a temperature of 10.3 +/- 0.4 degrees C (halibut) and 18.0 +/- 0.3 degrees C (turbot). Pharmacokinetic modeling of the data showed that metomidate had shorter elimination half-life and higher plasma concentrations in turbot compared with halibut, both species displaying a rapid uptake, distribution and excretion. Following intravenous administration, the volumes of distribution at steady state (Vd(ss)) were 0.21 L/kg (halibut) and 0.44 L/kg (turbot). Plasma clearances (Cl) were 0.099 L/h.kg in halibut and 0.26 L/h.kg in turbot and the elimination half-lives (t(1/2)lambdaz) were calculated to be 5.8 h and 2.2 h in halibut and turbot, respectively. Mean residence times (MRT) were 2.2 h in halibut and 1.7 h in turbot. Following oral administration, the t(1/2)lambdaz was 3.5 h in turbot. The maximum plasma concentration (Cmax) was 7.8 mg/L in turbot 1 h after administration. The oral bioavailability (F) was calculated to 100% in turbot. Following 5 min bath the maximum plasma concentrations (Cmax), which were observed immediately after end of the bath, were 9.5 mg/L and 13.3 mg/L in halibut and turbot, respectively. Metomidate rapidly immobilized the fish, with respiratory depression, reduced heart rate, and loss of balance/motor control within 1 min (mean). Recovery was slow, with resumed balance/motor control after 26.4 min. Opercular respiration movements were resumed more rapidly with a recorded mean of 1.7 min. Oral administration was demonstrated to be a way of immobilizing fish, for example in large aquariums, without exposing them to unwanted stress.

Inhibitory effects of etomidate and ketamine on endothelium-dependent relaxation in canine pulmonary artery.

BACKGROUND: The authors recently demonstrated that acetylcholine-induced pulmonary vasorelaxation had two primary components, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The goal was to investigate the effects of etomidate and ketamine on the NO- and EDHF-mediated components of pulmonary vasorelaxation in response to acetylcholine, bradykinin, and the calcium ionophore, A23187. METHODS: Canine pulmonary arterial rings with an intact endothelium were suspended in organ chambers for isometric tension recording. The effects of etomidate and ketamine (10(-5) M and 10(-4) M) on vasorelaxation responses to acetylcholine, bradykinin, and A23187 were assessed in phenylephrine-contracted rings. The NO- and EDHF-mediated components of relaxation were assessed using a NO synthase inhibitor (N-nitro-L-arginine methylester [L-NAME]: 10(-4) M) and a Ca2+-activated potassium channel inhibitor (tetrabutylammonium hydrogen sulfate [TBA]: 10(-3) M) in rings pretreated with a cyclooxygenase inhibitor (ibuprofen: 10(-5) M). Intracellular calcium concentration ([Ca2+]i) was measured in cultured bovine pulmonary artery endothelial cells loaded with acetoxylmethyl ester of fura-2. RESULTS: Etomidate and ketamine attenuated pulmonary vasorelaxation in response to acetylcholine and bradykinin, whereas they had no effect on the response to A23187. The relaxant responses to acetylcholine and bradykinin were attenuated by L-NAME or TBA alone and were abolished by combined inhibition in rings pretreated with ibuprofen. Etomidate and ketamine further attenuated both L-NAME-resistant and TBA-resistant relaxation. These anesthetics also inhibited increases in endothelial [Ca2+]i in response to bradykinin, but not A23187. CONCLUSION: These results indicate that etomidate and ketamine attenuated vasorelaxant responses to acetylcholine and bradykinin by inhibiting both NO- and EDHF-mediated components. Moreover, our results suggest that these anesthetics do not directly suppress NO or EDHF activity, but rather inhibit the endothelial [Ca2+]i transient in response to receptor activation.

A simple and efficient high-performance liquid chromatographic assay for etomidate in plasma.

The development and validation of an effective and simplified LC assay for the quantitation of etomidate in beagle plasma is described. The methodology employs a rapid and simple protein precipitation procedure in combination with previously reported chromatographic conditions. Using a 0.3 ml aliquot of plasma, the assay is linear in the concentration range of 50 to 5000 ng/ml, with an extraction efficiency between 97 to 104% and accuracy between 98 and 105%.

Relationship between etomidate plasma concentration and EEG effect in the rat.

PURPOSE: The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. METHODS: Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n=6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5-7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. RESULTS: A mean dose of 8.58+/-0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93+/-6 ml/min/kg, 4.03+/-0.24 l/kg and 59.4+/-10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65+/-0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44+/-0.03 microg/ml. CONCLUSIONS: The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5-7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.

Oral transmucosal etomidate in volunteers.

BACKGROUND: The oral transmucosal route of delivery is now used for many drugs, including fentanyl and midazolam. Etomidate's pharmacokinetic profile and physiochemical properties suggest it may be suitable for transmucosal delivery. Transmucosal delivery might extend etomidate's use to sedation and anxiolysis. This is the first study in humans to examine the oral transmucosal administration of a novel etomidate dosage form. METHODS: Ten healthy adult volunteers consumed 12.5-mg, 25-mg, 50-mg, and 100-mg doses of oral transmucosal etomidate (OTET) on four different study days. Serum etomidate concentrations, sedation, respiratory and cardiovascular variables, taste, and side effects were determined. RESULTS: Five minutes after OTET administration, etomidate was detected in the venous blood. Mean peak concentrations occurred 20-30 min later and ranged from 61-174 ng/ml, related to the dose administered. Drowsiness and light sleep occurred in a dose-related manner 10-20 min after administration and lasted for 30-60 min. No episodes of SpO2 <90%, hypotension, or emesis occurred at any dose throughout the study. Nausea was rare. Two volunteers exhibited a brief episode of involuntary tremor after the 100-mg dose. The bitter taste of OTET was judged increasingly unpleasant with escalating doses. CONCLUSIONS: Oral transmucosal etomidate produces dose-related increases in sedation and clinically significant serum concentrations with minimal side effects. The time course of these effects suggests that OTET might be useful when brief mild to moderate sedation with rapid recovery is desirable. Further development of this novel dosage form is warranted.

A comparison of two formulations for etomidate, 2-hydroxypropyl-beta-cyclodextrin (HPCD) and propylene glycol.

The unphysiologic osmolality of commercial preparations of etomidate dissolved in propylene glycol has limited its use as a drug to induce anesthesia. We wanted to determine whether hydroxypropyl-beta-cyclodextrin (HPCD) is a more suitable solvent than propylene glycol by comparing pharmacokinetics, pharmacodynamics, and side effects of etomidate preparations in each solvent. Twenty-four healthy, male volunteers, randomly assigned to either the male volunteers, randomly assigned to either the HPCD or the propylene glycol group received etomidate, 0.3 mg/kg, dissolved in one of the two test solvents. We recorded arterial blood pressure, heart rate, electrocardiogram, electroencephalogram, pain on injection, myoclonic movements, and venous sequelae. Systolic and diastolic blood pressure and heart rate were similar in both groups. Frequency and severity of pain on injection differed significantly between groups. In the propylene glycol group, five subjects suffered venous sequelae: in three, thrombophlebitis resolved after 5 days; in one, after 10 days; and in the other, after 12 days. In the HPCD group, only one subject suffered severe pain on injection and none had venous sequelae. We conclude that HPCD may be superior to propylene glycol as a solvent for etomidate. HPCD is associated with less pain, less thrombophlebitis, and no hemolysis without clinically important alteration of pharmacokinetics or pharmacodynamics of etomidate.

Comparison of infusion rates of three i.v. anaesthetic agents for induction in elderly patients.

We have compared the effect of different rates of injection of 2.5% thiopentone, 0.5% methohexitone and 0.2% etomidate for induction of anaesthesia in 90 premedicated, elderly patients. The agents were administered by infusion pump at rates of 1200 ml h-1, 600 ml h-1 and 300 ml h-1, respectively until anaesthesia was induced as judged by loss of verbal contact with the patient. The times for induction were significantly greater with the slower infusion rates (thiopentone 41 s, 57 s and 91 s (P < 0.001); methohexitone 44 s, 62 s and 84 s (P < 0.01); etomidate 48 s, 59 s and 87 s (P < 0.001)). The doses were significantly smaller (P < 0.001) with the slower infusion rates for all three agents (thiopentone 5.0, 3.7 and 2.8 mg kg-1; methohexitone 1.00, 0.75 and 0.56 mg kg-1; etomidate 0.26, 0.15 and 0.11 mg kg-1). For each drug there was no significant difference in induction characteristics, oxygen saturation, heart rate or mean arterial pressure, at the different infusion rates.