Metabolites Monoethylglycinexylidide Research Articles

This Month in Anesthesiology

This Month in Anesthesiology

Pharmacokinetics of Lidocaine and Its Metabolites Following Vaginal Administration of Lidocaine Gel to Healthy Female Subjects.

Lidocaine vaginal bioadhesive gel is being developed as a local anesthetic for use in minimally invasive outpatient gynecological procedures and was investigated in single‐dose and multiple‐dose studies in healthy young adult women. Lidocaine doses of 2.5%, 5%, and 10% (w/w) were administered, and parent drug and metabolites monoethylglycinexylidide and glycinexylidide were measured in plasma. Lidocaine was absorbed through vaginal tissue and into the systemic circulation in a dose‐proportional manner, and there was little systemic accumulation. Plasma concentrations were 10‐ to 20‐fold lower than concentrations obtained after administration of intravenous lidocaine used to treat arrhythmic activity, thus demonstrating a wide safety margin for a vaginal lidocaine product.

Upgrading of Wastewater Treatment Plants Through the Use of Unconventional Treatment Technologies: Removal of Lidocaine, Tramadol, Venlafaxine and Their Metabolites

The occurrence and removal efficiencies of the pharmaceuticals lidocaine (LDC), tramadol (TRA) and venlafaxine (VEN), and their major active metabolites monoethylglycinexylidide (MEGX), O-desmethyltramadol (ODT) and O-desmethylvenlafaxine (ODV) were studied at four wastewater treatment plants (WWTPs) equipped with activated sludge treatment technologies. In parallel to activated sludge treatment, the removal efficiency of the compounds in pilot- and full-scale projects installed at the WWTPs was investigated. Within these projects two different treatment methods were tested: adsorption onto powdered/granulated activated carbon (PAC/GAC) and ozonation. The metabolite MEGX was not detected in any sample. The concentrations of the target analytes in wastewater effluents resulting from activated sludge treatment ranged from 55 to 183 (LDC), 88 to 416 (TRA), 50 to 245 (ODT), 22 to 176 (VEN) and 77 to 520 ng L−1 (ODV). In the pilot project with subsequent treatment with PAC/GAC, the mean concentrations of the analytes were between

Lidocaine Metabolites Inhibit Glycine Transporter 1

Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms are not fully understood but glycinergic mechanisms might be involved. The synaptic glycine concentration is controlled by glycine transporters. Whereas neurons express two types of glycine transporters, astrocytes specifically express glycine transporter 1 (GlyT1). This study focuses on effects of lidocaine and its major metabolites on GlyT1 function. The effects of lidocaine and its metabolites monoethylglycinexylidide (MEGX), glycinexylidide, and N-ethylglycine on GlyT1 function were investigated in uptake experiments with [¹⁴C]-labeled glycine in primary rat astrocytes. Furthermore, the effect of lidocaine and its metabolites on glycine-induced currents were investigated in GlyT1-expressing Xenopus laevis oocytes. Lidocaine reduced glycine uptake only at toxic concentrations. The metabolites MEGX, glycinexylidide, and N-ethylglycine, however, significantly reduced glycine uptake (P < 0.05). Inhibition of glycine uptake by a combination of lidocaine with its metabolites at a clinically relevant concentration was diminished with increasing extracellular glycine concentrations. Detailed analysis revealed that MEGX inhibits GlyT1 function (P < 0.05), whereas N-ethylglycine was identified as an alternative GlyT1 substrate (EC₅₀ = 55 μM). Although lidocaine does not function directly on GlyT1, its metabolites MEGX and N-ethylglycine [corrected] were shown to inhibit GlyT1-mediated glycine uptake by at least two different mechanisms. Whereas N-ethylglycine [corrected] was demonstrated to be an alternative GlyT1 substrate, MEGX was shown to inhibit GlyT1 activity in both primary astrocytes and in GlyT1-expressing Xenopuslaevis oocytes at clinically relevant concentrations. These findings provide new insights into the possible mechanisms for the antinociceptive effect of systemic lidocaine.

Serum Concentrations of Lidocaine and Its Metabolites MEGX and GX During and After Prolonged Intravenous Infusion of Lidocaine in Horses after Colic Surgery

Lidocaine is the most commonly used prokinetic after gastrointestinal surgery in horses. Cardiovascular status, hepatic function, and duration of therapy are the primary determinants of lidocaine metabolism, and these factors could affect equine patients after colic surgery. This study examined the systemic concentrations of lidocaine and its active metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in horses that had undergone colic surgery and subsequently received prolonged postoperative lidocaine infusions. The mean lidocaine concentration increased over the course of treatment but did not exceed the therapeutic range. Concentrations of MEGX and GX increased progressively, and concentrations exceeding 1,000 ng/ml were observed frequently after 72 hours of infusion. None of the horses in the study developed severe signs of toxicity; however, the progressively increasing concentrations of lidocaine, MEGX, and GX are cause for concern in clinically ill patients receiving prolonged lidocaine therapy. The potential contribution of MEGX and GX should be considered when evaluating adverse reactions to prolonged lidocaine infusions.

Sensitive HPLC for simultaneous quantification of lidocaine and its metabolites monoethylglycinexylidide and glycinexylidide in serum

Sensitive HPLC for simultaneous quantification of lidocaine and its metabolites monoethylglycinexylidide and glycinexylidide in serum

Therapeutic serum lidocaine and metabolite concentrations in patients undergoing electrophysiologic study after discontinuation of intravenous lidocaine infusion

Serum concentrations of lidocaine and its metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were measured in seven patients after discontinuation of intravenous lidocaine necessary for control of spontaneous arrhythmias prior to electrophysiologic study. Standard loading doses of lidocaine were given intravenously followed by 2 mg/min infusions for 79.5 ± 6.5 hours. Electrophysiologic studies all started more than 5 half-lives or 7.5 hours after discontinuation of intravenous lidocaine. Local anesthesia with subcutaneous lidocaine (mean 162 ± 96 mg) was administered in six patients. Plasma concentrations of lidocaine and its metabolites were determined at the termination of the infusion, 2 and 4 hours afterwards, at the start of the electrophysiologic study prior to local anesthesia, and at the end of the study. Levels were also determined at 12 and 24 hours after discontinuation of the infusion. Mean plasma concentrations of lidocaine, MEGX, and GX at the start of the study were 1.02, 0.86, and 0.62 μg/ml, respectively. These had increased to 2.78, 0.92, and 0.68 by the end of the electrophysiologic study. One patient with coronary artery disease and prior out-of-hospital ventricular fibrillation had a therapeutic lidocaine level and no inducible arrhythmia at the time of the initial study. At a subsequent electrophysiologic study, no lidocaine or metabolites were detected in the serum and ventricular fibrillation was induced. Thus using the reported half-life of 90 minutes and discontinuing lidocaine 5 half-lives prior to electrophysiologic evaluation does not ensure lack of electrophysiologic effects of the parent compound or its metabolites. Lidocaine given for local anesthesia further increases lidocaine and metabolite levels. To avoid significant electrophysiologic sequelae, intravenous lidocaine should be discontinued for as long as possible prior to programmed stimulation. Local anesthesia with lidocaine should also be minimized or an alternate anesthetic agent should be used. Serum levels of lidocaine and its metabolites should be determined if electrophysiologic effects are suspected at the time of the study.

Changes in lignocaine disposition during long-term infusion in patients with acute ventricular arrhythmias.

Lignocaine disposition was studied in 30 patients with acute ventricular arrhythmias. Serum concentrations of lignocaine, its metabolites Monoethylglycine xylidide (MEGX) and glycine xylidide (GX), and alpha 1-acid glycoprotein (AAG) were analyzed during and after a 48-h lignocaine infusion. AAG concentrations tended to rise in patients with acute myocardial infarction (AMI), leading to binding of the drug in plasma. Lignocaine clearance was estimated at various times during the infusion using a Bayesian parameter estimation program and was found to decline over the course of the infusion. There was a significant reduction in clearance based on estimates obtained at the end of the infusion compared with estimates obtained during the first 0-5 h. Clearance was reduced both in patients who had an AMI and those who did not. Multiple linear regression analysis of the clearance data revealed that these changes could be described by a linear function of time and AAG concentration. These findings suggest that other factors in addition to protein binding changes may influence lignocaine disposition during long-term infusion.

Age-dependent lidocaine disposition in patients with acute myocardial infarction.

To evaluate age-dependent changes in lidocaine disposition in patients with acute myocardial infarction, we measured plasma concentrations of lidocaine and its metabolites monoethylglycinexylidide and glycinexylidide after discontinuation of a maintenance lidocaine infusion. Plasma lidocaine clearance was calculated by dividing the lidocaine concentration at the end of the infusion into the maintenance infusion rate. Lidocaine clearance in 35 patients was related to body weight and was reduced by heart failure. Heart failure was more common in the elderly, occurring in 15 of 27 (56%) patients over 65 years old and seven of 29 (24%) patients under 65 years old. There was a reduction in lidocaine clearance with age due, in part, to lower body weight and a higher prevalence of heart failure in the elderly. Multilinear regression analysis showed that age and weight contributed to the prediction of lidocaine plasma clearance in patients with and without heart failure. Age was a particularly important predictor of lidocaine clearance in patients with heart failure. Adjustment of lidocaine maintenance doses based on age, weight, and heart failure may help control the frequency of lidocaine adverse reactions in the elderly.

Maternal, fetal, and neonatal lidocaine levels following local perineal infiltration

Local infiltration of the perineum is a simple and commonly used technique for providing pain relief for episiotomy. It has always been considered safe and effective because a small amount of local anesthetic agent could be administered quickly and accurately to the perineum just prior to vaginal delivery and cord clamping. Because of the short time interval between local infiltration and delivery, very little anesthetic was thought to reach the fetus. However, the maternal and neonatal disposition of lidocaine following local perineal infiltration has not been well studied. The purpose of this study was to document placental transfer or nontransfer of lidocaine following local perineal infiltration. Fifteen normal parturient women at term and their infants were studied. After local perineal infiltration, the concentrations of lidocaine and two metabolites—monoethyl glycine xylidide and glycine xylidide—were determined in maternal plasma, in the umbilical cord vein at delivery, and in maternal and neonatal plasma or urine for 2 days post partum. Lidocaine and its metabolites were quantitated by gas chromatography-mass spectrometry. The pharmacologic results indicated the following: First, lidocaine is detected in maternal plasma as early as 1 minute after injection, and peak plasma concentrations occur within 3 to 15 minutes. Second, there is rapid placental transfer of lidocaine; the mean fetal/maternal ratio of 1.32 was significantly higher than that found following epidural anesthesia. Third, lidocaine and its active metabolites persisted in neonatal urine for at least 48 hours after delivery. This study suggests that local perineal infiltration with lidocaine for episiotomy should be considered similar to any other anesthetic technique in that it may result in significant neonatal drug exposure.