Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects.

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33-104.96% for the maximum plasma concentration (Cmax), 97.21-102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0-t), and 97.22-102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0-∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28-110.69% for the minimal BIS value (BISmin), 99.23-101.17% for the area under the BIS time curve from time 0-60 min after administration (BISAUC0-60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00-125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number: http://www.chinadrugtrials.org.cn/index.html . # CTR20191836.

Obstructive Jaundice does not Change the Population Pharmacokinetics of Etomidate in Patients who Underwent Bile Duct Surgery.

BACKGROUND: Etomidate is commonly used in the induction of anesthesia. We have previously confirmed that etomidate requirements are significantly reduced in patients with obstructive jaundice and that etomidate anesthesia during Endoscopic Retrograde Cholangiopancreatography (ERCP) results in more stable hemodynamics compared to propofol. The aim of the present study is to investigate whether obstructive jaundice affects the pharmacokinetics of etomidate in patients who underwent bile duct surgery. METHODS: A total of 18 patients with obstructive jaundice and 12 non-jaundiced patients scheduled for bile duct surgery were enrolled in the study. Etomidate 0.333 mg/kg was administered by IV bolus for anesthetic induction. Arterial blood samples were drawn before, during, and up to 300 minutes after the bolus. Plasma etomidate concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A nonlinear mixed-effects population modeling approach was used to characterize etomidate pharmacokinetics. The covariates of age, gender, height, weight, Body Surface area (BSA), Body Mass Index (BMI), Lean Body Mass (LBM), Total Bilirubin (TBL), Alanine Aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), creatinine (CR), and blood urea nitrogen (BUN) were tested for significant effects on parameters using a multiple forward selection approach. Covariate effects were judged based on changes in the Objective Function Value (OFV). RESULTS: A three-compartment disposition model adequately described the pharmacokinetics of etomidate. The model was further improved when height was a covariate of total clearance [Cl1=1.30+0.0232(HT-162), ΔOFV=-7.33; P<0.01)]. The introduction of any other covariates, including bilirubin and total bile acids, did not improve the model significantly (P>0.01). For the height of 162cm, the final pharmacokinetic parameter values were as follows: V1=1.42 (95% CI, 1.01-1.83, L), V2=5.52 (95% CI, 4.07-6.97, L), V3=63.9 (95% CI, 41.95-85.85, L),Cl1= 1.30 (95% CI, 1.19-1.41, L/min), Cl2= 1.21 (95%CI, 0.95-1.47, L/min), and Cl3=0.584 (95%CI, 0.95-1.21, L/min), respectively. CONCLUSION: A 3-compartment open model might best describe the concentration profile of etomidate after bolus infusion for anesthesia induction. The pharmacokinetics of etomidate did not change by the presence of obstructive jaundice.

Optimization, and in vitro and in vivo evaluation of etomidate intravenous lipid emulsion.

The aim of this investigation was to develop an etomidate intravenous lipid emulsion (ETM-ILE) and evaluate its properties in vitro and in vivo. Etomidate (ETM) is a hydrophobic drug, and organic solvents must be added to an etomidate injectable solution (ETM-SOL) to aid dissolution, that causes various adverse reactions on injection. Lipid emulsions are a novel drug formulation that can improve drug loading and reduce adverse reactions. ETM-ILE was prepared using high-pressure homogenization. Univariate experiments were performed to select key conditions and variables. The proportion of oil, egg lecithin, and poloxamer 188 (F68) served as variables for the optimization of the ETM-ILE formulation by central composite design response surface methodology. The optimized formulation had the following characteristics: particle size, 168.0 ± 0.3 nm; polydispersity index, 0.108 ± 0.028; zeta potential, -36.4 ± 0.2 mV; drug loading, 2.00 ± 0.01 mg/mL; encapsulation efficiency, 97.65% ± 0.16%; osmotic pressure, 292 ± 2 mOsmol/kg and pH value, 7.63 ± 0.07. Transmission electron microscopy images showed that the particles were spherical or spheroidal, with a diameter of approximately 200 nm. The stability study suggested that ETM-ILE could store at 4 ± 2 °C or 25 ± 2 °C for 12 months. Safety tests showed that ETM-ILE did not cause hemolysis or serious vascular irritation. The results of the pharmacokinetic study found that ETM-ILE was bioequivalent to ETM-SOL. However, a higher concentration of ETM was attained in the liver, spleen, and lungs after administration of ETM-ILE than after administration of ETM-SOL. This study found that ETM-ILE had great potential for clinical applications.

Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging.

Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting. Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer. Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO. Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO. Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.

Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700.

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores. METHODS: Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined. RESULTS: The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects. CONCLUSIONS: The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists.

Functional imaging of adrenal cortex. / Estudios de imagen funcional de la corteza adrenal.

The rising number of high-resolution imaging scans has increased the adrenal lesions detection, which require a differential diagnosis. Currently, the most commonly used scans are CT and MRI, but these are sometimes not very specific. In these cases, nuclear medicine scans with 131I-norcolesterol, 11C-metomidate and 18F-fludeoxyglucose help to differentiate benign vs. malignant lesions, to lateralize the involvement in hypersecretion disease, as well as to guide the therapeutic strategy in both unilateral and bilateral lesions.

The effect of midazolam or lidocaine administration prior to etomidate induction of anesthesia on heart rate, arterial pressure, intraocular pressure and serum cortisol concentration in healthy dogs.

OBJECTIVE: To evaluate selected effects of midazolam or lidocaine administered prior to etomidate for co-induction of anesthesia in healthy dogs. STUDY DESIGN: Prospective crossover experimental study. ANIMALS: A group of 12 healthy adult female Beagle dogs. METHODS: Dogs were premedicated with intravenous (IV) butorphanol (0.3 mg kg-1), and anesthesia was induced with etomidate following midazolam (0.3 mg kg-1), lidocaine (2 mg kg-1) or physiologic saline (1 mL) IV. Heart rate (HR), arterial blood pressure, respiratory rate (fR) and intraocular pressure (IOP) were recorded following butorphanol, after co-induction administration, after etomidate administration and immediately following intubation. Baseline IOP values were also obtained prior to sedation. Etomidate dose requirements and the presence of myoclonus, as well as coughing or gagging during intubation were recorded. Serum cortisol concentrations were measured prior to premedication and 6 hours following etomidate administration. RESULTS: Blood pressure, fR and IOP were similar among treatments. Blood pressure decreased in all treatments following etomidate administration and generally returned to sedated values following intubation. HR increased following intubation with midazolam and lidocaine but remained stable in the saline treatment. The dose of etomidate (median, interquartile range, range) required for intubation was lower following midazolam (2.2, 2.1-2.6, 1.7-4.1 mg kg-1) compared with lidocaine (2.7, 2.4-3.6, 2.2-5.1 mg kg-1, p = 0.012) or saline (3.0, 2.8-3.8, 1.9-5.1 mg kg-1, p = 0.015). Coughing or gagging was less frequent with midazolam compared with saline. Myoclonus was not observed. Changes in serum cortisol concentrations were not different among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam administration reduced etomidate dose requirements and improved intubation conditions compared with lidocaine or saline treatments. Neither co-induction agent caused clinically relevant differences in measured cardiopulmonary function, IOP or cortisol concentrations compared with saline in healthy dogs. Apnea was noted in all treatments following the induction of anesthesia and preoxygenation is recommended.

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.

Simultaneous Determination of Etomidate and Its Major Metabolite, Etomidate Acid, in Urine Using Dilute and Shoot Liquid Chromatography-Tandem Mass Spectrometry.

Etomidate (ET) is a commonly used sedative-hypnotic agent such as propofol to induce anesthesia, and it is rapidly metabolized to etomidate acid (ETA) in liver. Herein, a simple method to determine ET and ETA in urine simultaneously was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A simple sample preparation method reduced the total analysis time. For all analytes, the separation was achieved in 6.5 min using reversed-phase chromatography with gradient elution. The best separation and detection of ETA was achieved using a porous graphitic carbon column. The column temperature was maintained at 30 °C to improve the efficiency and sensitivity. The calibration curves were linear over the concentration ranges of 0.4-120.0 ng/mL (ET) and 1.0-300.0 ng/mL (ETA), obtained with a weighting factor of 1/x2. The coefficients of determination (r2) were greater than 0.9958. The lower limits of quantification were 0.4 ng/mL (ET) and 1.0 ng/mL (ETA), intra-day (n = 6) and inter-day (n = 24) precision values for all compounds were less than 10.2% and 8.4%, respectively, while the intra- and inter-day accuracies were in the -9.9-2.9%, and -7.0-0.6%. The applicability of the method was examined by analyzing the urine samples obtained from ET users.

Development of [18F]FAMTO: A novel fluorine-18 labelled positron emission tomography (PET) radiotracer for imaging CYP11B1 and CYP11B2 enzymes in adrenal glands.

INTRODUCTION: Primary aldosteronism accounts for 6-15% of hypertension cases, the single biggest contributor to global morbidity and mortality. Whilst ~50% of these patients have unilateral aldosterone-producing adenomas, only a minority of these have curative surgery as the current diagnosis of unilateral disease is poor. Carbon-11 radiolabelled metomidate ([11C]MTO) is a positron emission tomography (PET) radiotracer able to selectively identify CYP11B1/2 expressing adrenocortical lesions of the adrenal gland. However, the use of [11C]MTO is limited to PET centres equipped with on-site cyclotrons due to its short half-life of 20.4 min. Radiolabelling a fluorometomidate derivative with fluorine-18 (radioactive half life 109.8 min) in the para-aromatic position ([18F]FAMTO) has the potential to overcome this disadvantage and allow it to be transported to non-cyclotron-based imaging centres. METHODS: Two strategies for the one-step radio-synthesis of [18F]FAMTO were developed. [18F]FAMTO was obtained via radiofluorination via use of sulfonium salt (1) and boronic ester (2) precursors. [18F]FAMTO was evaluated in vitro by autoradiography of pig adrenal tissues and in vivo by determining its biodistribution in rodents. Rat plasma and urine were analysed to determine [18F]FAMTO metabolites. RESULTS: [18F]FAMTO is obtained from sulfonium salt (1) and boronic ester (2) precursors in 7% and 32% non-isolated radiochemical yield (RCY), respectively. Formulated [18F]FAMTO was obtained with >99% radiochemical and enantiomeric purity with a synthesis time of 140 min from the trapping of [18F]fluoride ion on an anion-exchange resin (QMA cartridge). In vitro autoradiography of [18F]FAMTO demonstrated exquisite specific binding in CYP11B-rich pig adrenal glands. In vivo [18F]FAMTO rapidly accumulates in adrenal glands. Liver uptake was about 34% of that in the adrenals and all other organs were <12% of the adrenal uptake at 60 min post-injection. Metabolite analysis showed 13% unchanged [18F]FAMTO in blood at 10 min post-administration and rapid urinary excretion. In vitro assays in human blood showed a free fraction of 37.5%. CONCLUSIONS: [18F]FAMTO, a new 18F-labelled analogue of metomidate, was successfully synthesised. In vitro and in vivo characterization demonstrated high selectivity towards aldosterone-producing enzymes (CYP11B1 and CYP11B2), supporting the potential of this radiotracer for human investigation.

Adding fentanyl to etomidate fails to reduce painful recall of external direct current cardioversion in adults: a randomised trial.

INTRODUCTION: External electrical cardioversion under hypnotics, even when combined with opioids, has been consistently described as distressing or painful. The main objective of the present study was to determine if adding an opioid to a hypnotic, in comparison to the same hypnotic alone, would decrease the incidence of unpleasant or painful recall during anaesthesia for external electrical cardioversion. METHODS: This was a single-centre, prospective, randomised, double-blinded clinical trial that took place from September 2011 to March 2012. Fifty-two adult patients with persistent atrial fibrillation, scheduled for external direct current cardioversion, were enrolled. Exclusion criteria were age >80 years, previous cardiac surgery, implanted pacemaker or defibrillator, and haemodynamic instability. Patients received intravenously either (group EF) fentanyl 50 g and after 60 s etomidate 0.1 mg/kg, or (group E) only etomidate 0.1 mg/kg. If the patients did not lose their eyelid reflex, repeated doses of etomidate 4 mg were given. Cardioversion was attempted with an extracardiac biphasic electrical shock from 200 to 300 J, at most three times. The primary endpoint was recall of something unpleasant or painful. Secondary outcome measures were predictors of the requirement for repeat doses of etomidate, and the number of shocks needed. RESULTS: Fifty-one patients (35 male, 16 female), aged 62.1 ± 10.2 years, completed the study. There were no differences between group EF and group E regarding recall (unpleasant recall 0 vs. 2 patients, p=0.235; painful recall 1 vs. 0 patients, p=0.510). The administration of etomidate alone was a significant predictor for subsequent repeated doses of etomidate (p=0.049, odds ratio 4.312, 95% confidence interval 1.007-18.460). The number of shocks needed to restore sinus rhythm did not differ between the groups (p=0.846). CONCLUSIONS: In the present study, the addition of fentanyl to etomidate did not diminish distressing or painful experience during anaesthesia for external cardioversion.

Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease.

BACKGROUND: Etomidate is a rapid-onset, short-acting hypnotic medication administered for the induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants are lacking. OBJECTIVE: The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery. METHODS: Four neonates and 16 infants, postnatal age 0.3-11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics. RESULTS: The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found significantly to impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 l/min/70 kg and 0.44 l/min/70 kg, respectively; central and peripheral distribution volume of 9.47 l/70 kgand 22.8 l/70 kg, respectively. Inter-individual variability was 94-142% for all parameters and the residual variability was 29%. CONCLUSIONS: The clearance of etomidate is lower in neonates and infants with congenital heart disease compared with published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population.

Advancing novel anesthetics: pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs.

BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation "soft" (i.e., metabolically labile) etomidate analogue. The purpose of this study was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. METHODS: CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. RESULTS: Compared with etomidate, CPMM was half as potent as a hypnotic (ED50 approximately 0.8 mg/kg), was more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 vs. 1,623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. CONCLUSION: The studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation.

Etomidate--a review of robust evidence for its use in various clinical scenarios.

Etomidate is an intravenous hypnotic with a favourable clinical profile in haemodynamic high-risk scenarios. Currently, there is an active debate about the clinical significance of the drug's side effects and its overall risk-benefit ratio. Etomidate-induced transient adrenocortical suppression is well documented and has been associated with increased mortality in sepsis. In surgical patients at risk of hypotensive complications, however, a review of current literature provides no robust evidence to contraindicate a single-bolus etomidate induction. Large randomised controlled trials as well as additional observational data are required to compare safety of etomidate and its alternatives.

Radiosynthesis of [124I]iodometomidate and biological evaluation using small-animal PET.

PURPOSE: The application of radiolabelled inhibitors of cytochrome P450 enzymes is a novel approach for molecular imaging of adrenocortical masses to detect adrenal tumours. One potential tracer is radiolabelled iodometomidate (IMTO) with a common option for scintigraphic diagnosis and therapeutic applications. The aim of this study was to radiolabel iodometomidate with the positron-emitting radionuclide iodine-124 ((124)I) for the investigation of the biological behaviour and pharmacokinetics with positron emission tomography (PET). PROCEDURES: [(124)I]IMTO has been synthesized by oxidative radioiodo-destannylation, purified via semi-preparative HPLC and formulated in acetate-buffered saline, which contained ascorbic acid and ethanol to avoid radiolytic decomposition. Biological evaluation was performed in rats which received 5.5 ± 0.7 MBq [(124)I]IMTO in vivo. The radioactivity distribution (n = 3) has been dynamically imaged from 0-120 min after intravenous (i.v.) injection by small-animal PET. Regions of interest have been defined manually in the reconstructed PET images, and the activity concentration was expressed as percent injected dose per gram tissue (%ID/g). RESULTS: [(124)I]IMTO was prepared with a radiochemical yield of 83 ± 5 % (n = 3) and a radiochemical purity of >97 %. The final formulation of [(124)I]IMTO was stable for up to 48 h at room temperature. Two hours after i.v. administration in rats, radioactivity concentration in the adrenal glands were 2.1 ± 0.3 %ID/g, which was sufficient to achieve highest-contrast adrenal PET images. CONCLUSIONS: In the present study, the biological characteristics of radioiodinated metomidate were evaluated. [(124)I]IMTO appears as an attractive PET tracer for imaging of adrenals.

Pros and cons of etomidate--more discussion than evidence?

PURPOSE OF REVIEW: To evaluate the most recent publications in the long-lived debate over the use of etomidate in critically ill septic and trauma patients. RECENT FINDINGS: Virtually without controversy is the hemodynamic stability after its use for induction of anesthesia on the one hand, and its negative effect on steroid synthesis on the other. The rating of the relative importance of both phenomena for the outcome of patients is however a highly controversial issue. We will discuss the most recent publications for two patient groups: trauma and critically ill septic patients. New meta-analyses and smaller studies have been published and might help us to weigh pros and cons in our patients. Sufficiently powered randomized controlled trials remain absent. The question whether supplemented corticosteroids after etomidate improve outcome is answered negatively by two recent studies. SUMMARY: A single dose of etomidate supplies good intubation conditions with hemodynamic stability, but increases the risk for adrenal insufficiency. The relative importance of these characteristics for the patients' outcome remains controversial, as there is a lack of direct evidence. According to the principle 'nihil nocere', reasoning argues against its use, especially in septic patients or in those at major risk to develop septic complications (e.g. trauma patients).

[¹²³I]Iodometomidate imaging in adrenocortical carcinoma.

CONTEXT: Imaging with [¹²³I]iodometomidate ([¹²³I]IMTO) has been shown to diagnose adrenocortical lesions with high sensitivity and specificity. OBJECTIVE: Our objective was to evaluate the clinical utility of [¹²³I]IMTO imaging in adrenocortical carcinoma (ACC). DESIGN: We conducted a prospective monocentric diagnostic study and a prospective case series at a single tertiary referral center. PATIENTS AND INTERVENTIONS: Fifty-eight patients with histologically confirmed ACC, all European Network for the Study of Adrenal Tumors stage IV (with distant metastases), received 185 MBq [¹²³I]IMTO. Sequential planar whole-body scans until 24 hours post injection and single photon emission computed tomography/computed tomography (SPECT/CT) hybrid imaging 4 to 6 hours post injection were performed. MAIN OUTCOME MEASURES: Outcome measures included uptake of [¹²³I]IMTO in ACC lesions, sensitivity and specificity of [¹²³I]IMTO imaging compared with conventional imaging, and number of patients eligible for [¹³¹I]IMTO therapy. RESULTS: Of 430 lesions detected by conventional imaging, 30% showed strong, 8% moderate, and 62% no tracer accumulation. [¹²³I]IMTO detected both primary and metastatic lesions of ACC. However, a substantial percentage of lesions failed to show [¹²³I]IMTO uptake. The overall sensitivity and specificity values were 38% and 100%, respectively. Thirty-four patients (59%) had at least 1 [¹²³I]IMTO-positive lesion. Cortisol and aldosterone secretion by ACC was positively correlated to [¹²³I]IMTO uptake (P = .01); cytotoxic chemotherapy and mitotane treatment presumably did not influence tracer uptake. Twenty-one patients (36.2%) had radiotracer uptake in all lesions ≥ 2 cm and therefore were potential candidates for targeted systemic radiotherapy with [¹³¹I]IMTO. CONCLUSION: About one-third of patients with ACC show specific retention of [¹²³I]IMTO in metastatic lesions. This study provides support for the conduct of a prospective trial to determine whether the first molecular informed therapy using [¹³¹I]IMTO will be of value to patients with metastatic ACC.

Novel etomidate derivatives.

Etomidate is a well established intravenous anaesthetic agent which has been widely used. Recognised limitations of the agent include adrenocortical suppression, myoclonus and post-operative nausea and vomiting, PONV. MOC-etomidate, carboetomidate and MOC-carboetomidate are novel etomidate derivatives. Their preclinical data and their potential for human administration are critically reviewed. 'Soft' pharmacology (rapid ester hydrolysis) limits the duration of action of MOC-etomidate and MOC-carboetomidate giving them rapid offset after administration is discontinued. Adrenocortical depression is minimised either by ester hydrolysis or by structural change to the etomidate molecule. Potential limitations include the yet to be determined incidence of myoclonus and PONV if these new agents are administered to humans.

Electroencephalographic recovery, hypnotic emergence, and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats.

BACKGROUND: Methoxycarbonyl etomidate is an ultrarapidly metabolized etomidate analog. It is metabolized to methoxycarbonyl etomidate carboxylic acid (MOC-ECA), which has a hypnotic potency that is 350-fold less than that of methoxycarbonyl etomidate. The authors explored the relationships between methoxycarbonyl etomidate infusion duration, recovery time, metabolite concentrations in blood and cerebrospinal fluid (CSF), and methoxycarbonyl etomidate metabolism in brain tissue and CSF to test the hypothesis that rapid metabolism of methoxycarbonyl etomidate may lead to sufficient accumulation of MOC-ECA in the brain to produce a pharmacologic effect. METHODS: A closed-loop system with burst suppression ratio feedback was used to administer methoxycarbonyl etomidate infusions of varying durations to rats. After infusion, recovery of the electroencephalogram and righting reflexes were assessed. MOC-ECA concentrations were measured in blood and CSF during and after methoxycarbonyl etomidate infusion, and the in vitro half-life of methoxycarbonyl etomidate was determined in rat brain tissue and CSF. RESULTS: Upon termination of continuous methoxycarbonyl etomidate infusions, the burst suppression ratio recovered in a biexponential manner with fast and slow components having time constants that differed by more than 100-fold and amplitudes that varied inversely with infusion duration. MOC-ECA concentrations reached hypnotic concentrations in the CSF with prolonged methoxycarbonyl etomidate infusion and then decreased during a period of several hours after infusion termination. The metabolic half-life of methoxycarbonyl etomidate in brain tissue and CSF was 11 and 20 min, respectively. CONCLUSION: In rats, methoxycarbonyl etomidate metabolism is sufficiently fast to produce pharmacologically active MOC-ECA concentrations in the brain with prolonged methoxycarbonyl etomidate infusion.

Population pharmacokinetics of intravenous bolus etomidate in children over 6 months of age.

BACKGROUND: Information has been very limited on the population pharmacokinetics (PK) of etomidate in pediatric patients. The purpose of this study was to characterize the PK of etomidate in children. METHODS: Forty-nine children aged over 6 months undergoing elective surgery received etomidate 0.3 mg·kg(-1) bolus i.v. within 15 s for anesthesia induction. Arterial blood samples were collected for 2 h after injection. A population nonlinear mixed effects modeling approach was used to characterize etomidate PK. Estimates were standardized to a 70-kg adult using allometric size models. RESULTS: Children had a median age of 4 years (0.53-13.21 years) and weight 15.7 kg (7.5-52 kg). PK of etomidate was best estimated using a three-compartment model with weight on systemic (Cl(1)) and inter-compartmental clearances (Cl(2), Cl(3)), central (V(1)), and peripheral compartment volumes (V(2), V(3)). The most significant PK covariate was age, with increasing age having reduced size-adjusted Cl(1), V(1), and V(3) (all P < 0.01). The estimates of PK parameter (standardized to 70-kg adult) for a typical 4-year-old children were Cl(1) = 1.50 l·min(-1), Cl(2) = 1.95 l·min(-1), Cl(3) = 1.23 l·min(-1), V(1) = 9.51 l, V(2) = 11.0 l, and V(3) = 79.2 l, respectively. CONCLUSIONS: Owing to enhanced clearance and increased central compartment volume of etomidate, smaller (younger) children will require higher etomidate bolus dose than larger (older) children to achieve equivalent plasma concentrations. The dependence of Cl(1) and V(1) on age does not support weight-based etomidate dosing in smaller children.