Monoethylglycinexylidide Research Articles

The use of lidocaine as a test of liver function in liver transplantation.

The hepatic metabolism of lidocaine to monoethyl-glycinexylidide (MEGX) is the basis of a dynamic test of liver function. To understand its potential value in liver transplantation, the latter has been considered in the following three separate stages: pretransplantation assessment of potential candidates, potential liver donors, and the transplant recipient. In pretransplantation patients, data support its role in assessing risk of morbidity and mortality. In assessment of the liver transplant donor, there are differences concerning apparent usefulness, and these must be resolved. In the liver transplant recipient, serial measurements are useful to measure real-time hepatic metabolic activity. Low MEGX values reflect the clinical condition of the patient, and the importance of entirely assessing the patient, not just noting the test result, is paramount. This review has considered the role of the MEGX test in liver transplantation.

Increasing Splanchnic Blood Flow in the Critically III

To assess the effect of low dose dopexamine and dopamine on splanchnic blood flow as measured by gastric intramucosal pH, hepatic metabolism of lidocaine (lignocaine) to monoethylglycinexy-lidide (MEGX), and plasma disappearance rate of indocyanine green (ICG). Single-blind randomization of patients with a gastric intramucosal acidosis to receive dopexamine (ten patients), dopamine (ten patients), or saline solution (five control patients) for 2 h. All 25 patients were in the ICU of Guys' Hospital. All patients met the criteria for the diagnosis of the systemic inflammatory response syndrome, were mechanically ventilated, and had pulmonary artery catheters placed. All had a low gastric intramucosal pH and had a median first 24-h acute physiology and chronic health evaluation (II) score of 22 (range, 7 to 40). Baseline measurements of gastric intramucosal pH, MEGX formation from lidocaine, ICG plasma disappearance rate, heart rate, mean arterial pressure, pulmonary artery occlusion pressure, cardiac index, oxygen delivery index, oxygen uptake index, systemic vascular resistance, and arterial pH were taken. Dopexamine (1 mg.kg-1.min-1), dopamine (2.5 mg.kg-1.min-1), or 0.9% saline solution was then infused for 2 h, after which a repeated set of the measurements was taken. Dopexamine at a low dose had no effect on any of the systemic measurements. The median intramucosal pH rose from 7.23 to 7.35 (p < 0.005), the median ICG plasma disappearance rate from 7.6 to 11.3%.min-1 (p < 0.02), and the median MEGX concentration from 4 to 10.2 ng.mL-1 (p < 0.005). Dopamine had no effect on any of the measured variables. There were no changes in the control group. Low-dose dopexamine increases splanchnic blood flow as measured by gastric intramucosal pH, MEGX formation from lidocaine, and ICG clearance. The lack of any change in the systemic measurements suggests that these effects are the result of a selective vasodilatation of the splanchnic vessels. At the dose used in this study, dopamine had no effect on splanchnic blood flow. Dopexamine may be useful in the management of splanchnic ischemia in the critically ill.

Preliminary assessment of glycine conjugation of para-aminobenzoic acid as a quantitative test of liver function

Our hypothesis is that because of its hepatic metabolism paraaminobenzoic acid (PABA) could be a test of liver function. PABa is well absorbed by the gastrointestinal tract and acetylated and conjugated in the liver to glycine before being excreted. Its three major metabolites include para-acetoamidobenzoic acid (PAABA), paraaminohippuric acid (PAHA), and paraacetamidohippuric acid (PAAHA). In this study, we measured the metabolism of lidocaine to monoethylglycinexylidide (MEGX) and PABA to PAHA + PAAHA/PABA + PAABA + PAHA + PAAHA (hippurate ratio) in 14 patients with liver disease and 12 control subjects. Comparison of the total bilirubin with the hippurate ratio (at 30 min) and the conventional MEGX test (at 15 min) was assessed. The 30 min hippurate ratio correlated well with the 15 min MEGX results ( r = 0.69). While these results are preliminary the PABA test appears to be equally sensitive to MEGX and has the distinct advantage over the MEGX test of being administered orally versus the intravenous administration of lidocaine which is often associated with unwanted side-effects such as hypotension, drowsiness and paresthesias.

Novel ornithine decarboxylase protein in human hepatocellular carcinoma: [formula omitted] Third Dept. of Internal Medicine, Second Dept. of Biochemistry, and Second Dept. of Surgery, Osaka City University Medical School, Osaka 545, Japan

Topical lidocaine has been recently marketed as a new treatment for post-herpetic neuralgia. The aim of our study was to characterize the absorption profile of and systemic exposure to lidocaine from patch and gel formulations in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. The bioavailability of lidocaine from the patch formulation averaged 3%, and was similar after single and repeated doses. Systemic exposure to lidocaine and monoethylglycinexylidide (MEGX), the primary active metabolite of lidocaine, after application of lidocaine gel or patches was minimal in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. Considering the benefit versus risk of topical lidocaine, systemic absorption and toxicity of lidocaine seems not to be a signi ficant risk. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1343–1350, 2002

Monoethylglycinexylidide Formation as an Independent Measure of Warm Hepatic Ischemia and Reperfusion Injury

An accurate serologic measure of hepatic function would be clinically useful in selecting donors for liver transplantation. An experimental model that incorporates varying lengths of total hepatic warm ischemia with reperfusion injury was utilized to compare serologic parameters and mitochondrial performance of oxidative phosphorylation in predicting hepatocellular injury. Monoethylglycinexylidide (MEGX) formation following bolus intravenous lidocaine injection was found to be significantly decreased (P < 0.0001) at all periods of ischemia when compared to that in nonischemic controls. A serum MEGX level of <50 μg/liter suggested severe hepatic damage. No correlation was found between MEGX level and liver viability as measured by animal survival. Serum transaminase (AST and ALT) levels demonstrated progressive, nonsignificant elevations with increasing length of ischemia (P = 0.0779 at the maximum ischemic time). Polarographic measurements of mitochondrial oxidative phosphorylation did not reveal a significant alteration in subcellular metabolism with prolonged ischemic time. These data highlight the comparative sensitivity of MEGX formation as an early quantitative measurement of hepatocellular injury during warm ischemia, although it was not predictive of organ viability.

Pharmacokinetics of lidocaine and its major metabolite- monoethylglycinexylidide (MEGX) in rabbits with experimental common bile duct obstruction.

The aim of this study was to evaluate, using an experimental model, the effect of obstructive cholestasis on the pharmacokinetics of lidocaine and the formation rate of its major metabolite- monoethylglycinexylidide (MEGX)-in rabbits. The investigation was carried out on 20 rabbits, randomly divided into two groups: a control one sham-operated and an experimental one-animals with biliary duct ligation. The measurements, i.e. laboratory and pharmacodynamic tests, as well as pharmacokinetic assays were performed prior to the operation as well as 10-12 days after the bile duct ligation. At the end stage of the study, livers were examined macro- and microscopically and biochemical analysis of the liver microsomes were performed. Lidocaine was given intravenously, as a bolus of 6 mg/kg. Blood for pharmacokinetic assay was sampled within 6 h following the drug administration, and MEGX concentration was evaluated 15 min after lidocaine had been administered. The immunofluorescence polarization method was employed for determination of lidocaine and MEGX concentrations. The one-compartment open model was used for calculations.

The Monoethylglycinexylidide Test Is More Useful for Evaluating Liver Function Than Indocyanine Green Test

Lidocaine was used for evaluation of hepatic function in a patient undergoing hepatic resection. Preoperatively, half-life of indocyanine green (ICG) was 33 min after intravenous administration. Plasma concentration of the N-dealkylated metabolite of lidocaine, monoethylglycinexylidide (MEGX), was quantitatively determined to evaluate hepatic function. The patient's rate of formation of MEGX at 15 min after administration of lidocaine was within normal limits, at 56 micrograms/L. These findings suggest that in this patient, hepatic cytochrome P-450IIIA activity was not impaired, but selective impairment of uptake of ICG into hepatocytes or excretion into the bile ducts was present. The rate of formation of MEGX was decreased, and plasma concentration of bilirubin was elevated postsurgically; this could have been the result of decreased cytochrome P-450IIIA activity or decreased hepatic blood flow after hepatic resection. We conclude that the rate of formation of MEGX is a better index of hepatic function than is ICG half-life.

Monoethylglycinexylidide as an early predictor of posttraumatic multiple organ failure.

The prognostic value of a dynamic liver-function test, based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX), in predicting multiple organ failure (MOF) was prospectively investigated in 28 critically ill patients after multiple trauma. The MEGX test and conventional static liver tests (bilirubin, aspartate aminotransferase, glutamate dehydrogenase, and factor V) were performed on days 1, 3, 5, and 7 after trauma. Patients were classified by a modified MOF score into a group without (n = 18) and a group with the MOF syndrome (n = 10). One patient who developed MOF on the basis of a bacterial septicemia was excluded from the general evaluation. No significant differences were observed in the MEGX values of the two groups on day 1. All patients who subsequently developed MOF, however, displayed a sharp decrease in their MEGX values between days 1 and 3. Analysis of the data using receiver operating characteristic (ROC) curves revealed that the results of the MEGX test on day 3 provided the greatest discriminating power between patients with and without subsequent MOF. A cut-off MEGX value of 30 micrograms/L on day 3 was associated with a prognostic sensitivity of 89% and a prognostic specificity of 94%.

Functional staging of chronic liver diseases by means of monoethylglycinexylidide (MEGX) formation: [formula omitted], N. Campo, S. Caglieris, S. Alvarez, L. Arzani, S. Borzone, D. Risso, P.B. Lantieri, G. Celle, DI.M.I., Gastroenterology Unit, University of Genoa, Italy

Functional staging of chronic liver diseases by means of monoethylglycinexylidide (MEGX) formation: [formula omitted], N. Campo, S. Caglieris, S. Alvarez, L. Arzani, S. Borzone, D. Risso, P.B. Lantieri, G. Celle, DI.M.I., Gastroenterology Unit, University of Genoa, Italy

Effect of dehydration and hyperosmolal hydration on lignocaine and metabolites disposition in conscious rabbits.

1. The present study aimed to investigate the effect of dehydration and hyperosmolal hydration on the disposition of lignocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). 2. Lignocaine was infused to three groups of conscious rabbits: controls, rabbits previously deprived of water for 48 h and rabbits receiving an infusion of 2.5% NaCl. 3. In dehydrated and hyperosmolal-hydrated rabbits, plasma osmolality was 321 +/- 1 and 313 +/- 1 mOsm kg-1, respectively (P < 0.01 compared to controls, 285 +/- 1 mOsm kg-1). In dehydrated animals, baseline values of plasma arginine vasopressin (AVP) concentrations and plasma renin activity (PRA) were higher than in controls, i.e. 12.4 +/- 1.4 pg ml-1 and 15.4 +/- 1.7 ng AI ml-1 h-1 vs. 3.4 +/- 0.2 pg ml-1 (P < 0.01), and 5.1 +/- 0.6 ng AI ml-1 h-1 (P < 0.01), respectively; atrial natriuretic peptide (ANP) decreased from 55 +/- 11 to 32 +/- 4 pg ml-1 (P < 0.05). Compared to controls, hyperosmolal hydration only increased AVP to 15.5 +/- 0.7 pg ml-1 (P < 0.01). 4. Under both experimental conditions, lignocaine plasma concentrations were almost double (P < 0.01) those in controls, due to a lower systemic clearance, e.g. 54 +/- 3 and 59 +/- 1 vs. 96 +/- 5 ml min-1 kg-1, respectively. Plasma levels of MEGX increased (P < 0.01) only in dehydrated animals, although GX plasma concentrations were augmented (P < 0.01) about three fold in both groups of animals. The changes in lignocaine plasma concentrations were correlated with AVP levels (R2 = 0.5168, P<0.001).5. To document the effect of AVP on hepatic plasma flow, another group of rabbits received on separate occasions two doses of AVP (17 and 84 ng kg-1) while receiving an infusion of in docyanine green. AVP reduced hepatic plasma flow from 38.9 +/-2.7 ml min-1 to 19.6 +/-2.5 ml min-1 (P<0.01).The predicted maximal AVP-induced decrease in hepatic plasma flow was 19.6 ml min-1 kg- 1(Emax), and AVP concentration eliciting 50% of Em.. (ED50) was 28.7 pg ml-1.6 It is concluded that both dehydration and hyperosmolal hydration alter the disposition of lignocaine and two of its metabolites.

Influence of Gender on the Monoethylglycinexylidide Test in Normal Subjects and Liver Donors

The objective of this study was to investigate the effect of gender on monoethylglycinexylidide (MEGX) formation in normal subjects and cadaveric liver donors. The study included 92 male and female healthy volunteers < 45 years of age and 98 age- and sex-matched liver donors from a previous study, whose livers were used for transplantation. Women < 45 years not taking contraceptives showed significantly lower MEGX concentrations 30 min after lidocaine administration than men [median (16-84th percentile)]: 59 micrograms/L (41-70 micrograms/L) versus 81 micrograms/L (58-98 micrograms/L)]. The lowest MEGX 30 min values were observed in women taking contraceptives: 39 micrograms/L (25-48 micrograms/L). Intraindividual variability of serial MEGX tests was moderate (median: 17.8%, n = 8) when measured in female subjects taking no contraceptives and males. Cadaveric liver donors showed significantly higher MEGX 15 and 30 min values compared with normal subjects (p < or = 0.0001). There was no statistically significant difference between MEGX values obtained in male and female cadaveric donors. The urinary excretion of MEGX was similar in male and female normal subjects. Our results suggest that sex-related differences in MEGX formation as well as the influence of contraceptives have to be taken into account when test results from living related liver donors and patients with less advanced chronic liver disease are evaluated. In cadaveric liver donors, however, sex-related differences do not affect MEGX formation.

The role of dynamic and morphological studies in the assessment of potential liver donors.

In a prospective study, 66 donor livers were evaluated by monoethylglycinexylidide (MEGX) dynamic clearance and semiquantitative scoring of pathological changes in liver biopsies. The median MEGX level in 63 donors was 89 mcg/L (range 16-250 mcg/L); fifteen had MEGX levels < 50 mcg/L, 17 between 50 and 90 mcg/L, and 31 > 90 mcg/L. There were no cases of primary nonfunction, and no deaths were related to poor graft function. There was no statistically significant difference in peak aspartate aminotransferase (AST), day 5 AST, peak bilirubin, or lowest prothrombin time among the 3 groups. Liver biopsies were assessed in 61 donors: 33 (54%) were normal and 17 (28%) showed mild, 8 (13%) showed moderate, and 3 (5%) showed severe steatosis. Postperfusion biopsy assessing the extent of preservation injury was essentially normal or showed minimal change in 16 (26%), mild change in 29 (48%), moderate in 13 (21%) and severe abnormalities in 3 (5%). The latter 3 biopsies all had severe steatosis. There was no significant difference in early graft function or outcome between moderate/severe groups and normal/minimal groups, although the former had a higher peak AST (P < 0.02) and peak bilirubin (P < 0.004). This detailed prospective analysis suggests that MEGX and the morphological studies may assist in the assessment of potential liver donors but they do not provide a basis on which grafts should be discarded.

The effect of liver disease and food on plasma MEGX concentrations.

Plasma monoethylglycinexylidide (MEGX) concentrations were measured in 15 healthy controls (age 23-46 years) and 12 patients with biopsy proven cirrhosis (age 34-70 years) 30 min after 1 mg kg-1 intravenous lignocaine. Mean (+/- s.d.) MEGX concentrations were 57 +/- 33 ng ml-1 in the controls compared with 21 +/- 18 ng ml-1 in the cirrhotics (P < 0.05), but there was overlap in the range of concentrations. MEGX concentrations were inversely correlated with age, but not disease severity, in the cirrhotic patients (r = 0.62, P = 0.04) but not in the control subjects. In a second study 20 healthy subjects were given 1 mg kg-1 intravenous lignocaine on two occasions; either fed or fasted, and samples taken at 15, 30 and 60 min after dosage. MEGX concentrations were not significantly different at any time within either day or between fed and fasted study days. There was no correlation with age. The plasma lignocaine concentration at 15 min was significantly higher fed than fasted (2.88 +/- 2.44 and 1.82 +/- 0.96 micrograms ml-1, P = 0.01). Measurement of plasma MEGX after i.v. lignocaine is a useful test of liver function and may be performed in fed or fasted subjects. It is reproducible within an individual but is not specific for cirrhosis and appears age-related in liver disease.

Metabolism of lidocaine by rat pulmonary cytochrome P450

The metabolism of lidocaine was studied using microsomes from extrahepatic tissues of rats, including lung, kidney and brain, or using a reconstituted system with purified CYP2B1 and CYP4B1. Rat pulmonary microsomes metabolized lidocaine to an N-deethylated metabolite, monoethylglycinexylidide (MEGX). Renal microsomes produced MEGX and 3-hydroxylidocaine (3-OH LID), although the rate of MEGX formation was much lower in renal than in pulmonary microsomes. Other metabolites were not detected. Lidocaine was not metabolized by brain microsomes. In extrahepatic tissues, pulmonary microsomes had the highest activity. Hence, two major forms of cytochrome P450 isozymes, CYP2B1 and CYP4B1, in rat pulmonary microsomes were used for further study. The study with a reconstituted system using purified cytochrome P450 isozymes revealed that only CYP2B1 showed lidocaine deethylation activity; the other form of cytochrome P450 in the lung, CYP4B1, did not. The Michaelis-Menten constant for lidocaine N-deethylation by rat pulmonary microsomes was 0.27 mM. Antibody against CYP2B1 completely inhibited the formation of MEGX by pulmonary microsomes. These results suggest that lidocaine is metabolized by rat lung, including CYP2B1.

Formation rate of monoethylglycinexylidide (MEGX) in normal subjects and patients with chronic liver diseases

Formation rate of monoethylglycinexylidide (MEGX) in normal subjects and patients with chronic liver diseases

Use of monoethylglycinexylidide as a liver function test in the liver transplant recipient.

The hepatic conversion of lignocaine to monoethylglycinexylidide (MEGX) has been used as a real time monitor of liver function in liver transplant recipients. Data are reported for the first 4 weeks after transplant in 50 consecutive orthotopic liver grafts in 47 adults. The MEGX concentration was significantly depressed by approximately 50% in those patients in whom there was a complicated clinical course (excluding steroid-sensitive rejection) after transplantation, compared with patients in whom major complications did not occur. The MEGX concentration in the recipients after transplant was independent of the donor MEGX concentration, but, in addition to the patient's clinical status, was strongly influenced by the recipients pretransplant biochemical profile, being inversely related to the pretransplant bilirubin concentration. MEGX concentrations < 25 micrograms/L in the first 36 hr after revascularization were predictive of greater morbidity and mortality.

THE UNRELIABILITY OF THE LIDOCAINE/MONOETHYLGLYCINEXYLIDIDE TEST FOR ASSESSMENT OF LIVER DONORS

The serum monoethylglycinexylidide (MEGX) level 15 min (t15) after i.v. administration of lidocaine (1 mg/kg) in liver donors was retrospectively correlated with graft outcome and early hepatic function. Among the 35 orthotopic liver transplants studied, 4 recipients had to be retransplanted within 10 days post-OLT because of early graft nonfunction or dysfunction, and 3 recipients died, with a median (range) donor MEGX t15 (ng/ml) of 100 (86-119) and 169 (146-182), respectively. The remaining 28 OLT patients living with functioning grafts had a donor MEGX of 87 (18-245). No significant correlations could be found between donor MEGX t15 and recipient mean and peak glutamic-oxaloacetic and -pyruvic transaminases, total serum bilirubin, or mean and minimum prothrombin time values studied from day 1 to day 5 post-OLT. Moreover, categorization of donors using the MEGX t15 cut-off point of 80 ng/ml could not predict liver graft quality, as previously suggested. In summary, MEGX t15 in liver donors correlated neither with graft outcome nor with early functional parameters. Accordingly, the MEGX test should not be used as an isolated discriminatory evaluation for organ utilization.

Hepatic lidocaine metabolism and complications of cirrhosis. Implications for assessing patient priority for hepatic transplantation.

The number of patients awaiting hepatic transplantation continues to exceed organ donation. As a result, many liver transplant candidates will develop life-threatening complications of their liver disease and not survive the pretransplant waiting period. Recent studies have demonstrated that hepatic lidocaine metabolism into monoethylglycinexylidide (MEG-X) can predict pretransplant survival. The present study was performed to determine if MEG-X could also predict pretransplant complications and thereby be useful in stratifying persons being evaluated for hepatic transplantation. A total of 57 patients with biopsy-proven cirrhosis underwent MEG-X testing. Of 57 patients, 30 (53%) developed life-threatening complications of their liver disease--i.e., variceal bleeding, grade II hepatic encephalopathy or worse, and spontaneous bacterial peritonitis. MEG-X values were greater in persons without complications of liver disease than in persons with complications (25.7 +/- 2.9 versus 14.7 +/- 1.4 ng/ml, respectively). No patients with MEG-X greater than 30 ng/ml developed a major complication. No significant difference in any of the standard liver function tests existed between persons who developed complications and patients who did not. In this group of 57 patients, 4 (7%) died from complications of cirrhosis. Mean MEG-X for patients who died (5.5 +/- 1.6 ng/ml) was significantly less (P < 0.05) than observed for other patient groups. All patients who died had MEG-X values below 10 ng/ml. This suggests that MEG-X testing could be an extremely useful test in the evaluation of patients for hepatic transplantation by identifying persons at increased risk for developing complications of chronic liver disease.

Measurement of Monoethylglycinexylidide (MEGX) as an Index of Donor Liver Function

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Evaluation of the liver function of cirrhotic patients based on the formation of monoethylglycine xylidide (MEGX) from lidocaine.

Determination of the functional hepatic reserve is still controversial. Many tests have been proposed, but the assay based on formation of the lidocaine metabolite, monoethylglycine xylidide, seems to offer a promising approach to this problem. In this study we evaluated the effectiveness of the monoethylglycine xylidide test in the clinical evaluation of 31 cirrhotic patients submitted to three different therapeutic options (sclerotherapy, transjugular intrahepatic protosystemic shunt and surgical procedures) and in 1 patient submitted to right hepatectomy for giant hepatic angioma. We found a statistically significant difference between Child A and C patients and between Child B and C patients. The test did not differentiate Child A from Child B patients. We found no correlation between the Child-Pugh score, serum bilirubin, albumin and prothrombin time. There were no differences among the three groups of patients that could be statistically related to their therapy. The monoethylglycine xylidide test seems to be an attractive alternative to previous methods for the evaluation of the functional hepatic reserve, but further studies are necessary to assess the prognostic value of the test in cirrhotics, to separate the independent contribution of portosystemic shunting and hepatocyte dysfunction to monoethylglycine xylidide formation, and to evaluate the test as a prognostic index in cirrhotic patients submitted to general surgery.