Monoethylglycinexylidide Formation Research Articles

Dietary-Induced Obesity, Hepatic Cytochrome P450, and Lidocaine Metabolism: Comparative Effects of High-Fat Diets in Mice and Rats and Reversibility of Effects With Normalization of Diet

The effects of a high-fat diet on mRNA and protein of cytochrome P450 (CYP) enzymes in rats and mice and its impact on lidocaine deethylation to its main active metabolite, monoethylglycinexylidide (MEGX), in rats were investigated. The effect of a change in diet from high-fat to standard diet was also evaluated. Plasma biochemistry, mRNA, protein expression for selected CYP, and the activity of lidocaine deethylation were determined. The high-fat diet curtailed the activity and the expression of the majority of CYPs (CYP1A2, CYP3A1, CYP2C11, CYP2C12, and CYP2D1), mRNA levels (Cyp1a2 and Cyp3a2), and MEGX maximal formation rate (Vmax). Mice showed complementary results in their protein expressions of cyp3a and 1a2. Switching the diet back to standard chow in rats for 4 weeks reverted the expression levels of mRNA and protein back to normal levels as well as the maximum formation rates of MEGX. Female and male rodents showed similar patterns in CYP expression and lidocaine metabolism in response to the diets, although MEGX formation was faster in male rats. In conclusion, diet-induced obesity caused general decreases in CYP isoforms not only in rats but also in mice. The effects were shown to be reversible in rats by normalizing the diet.

Effect of erythromycin and rifampicin on monoethylglycinexylidide test

Background:The dynamic liver function test based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX) provides a direct measure of the actual functional state of the liver. Cytochrome P450 (CYP) 3A4 has been proposed as the main CYP isoform responsible for MEGX formation. The concomitant use of either CYP3A4 inducer rifampicin or CYP3A4 inhibitor erythromycin may influence the results of MEGX test. Hence, the objective of this study was to evaluate the effect of a CYP3A4 inhibitor erythromycin and inducer rifampicin on the MEGX test.Materials and Methods:The study included 20 healthy male volunteers whose routine laboratory tests were normal. As per study protocol, MEGX test was carried out in all the participants after an overnight fast. All the participants were given 1 mg/kg lidocaine dose intravenously and MEGX concentration at 30 and 60 min after IV dose was measured using HPLC. These MEGX values served as control values. Ten subjects received 600 mg/day erythromycin orally for six days while remaining ten participants received 600 mg/day rifampicin orally for six days. On the sixth day, MEGX test was carried out two hours after the last dose.Result:Rifampicin increased the mean plasma concentration of MEGX30 from 93.94 ± 26.31 to 98.54 ± 24.94 μg/ml (P = 0.085) and MEGX60 from 134.34 ± 35.42 to 136.36 ± 33.14 μg/ml (P = 0.051). Erythromycin lowered the serum concentration of MEGX30 from 101.37 ± 39.39 to 96.67 ± 36.09 μg/ml (P = 0.128) and MEGX60 from 142.52 ± 42.65 to 138.98 ± 40.23 μg/ml (P = 0.159).Conclusion:It can be concluded from this study that the MEGX test is not affected by concomitant administration of CYP3A4 modifiers rifampicin and erythromycin.

Assessment of hepatic reserve for indication of hepatic resection: how I do it

Hepatic resection may result in liver failure in patients with cirrhotic livers. Preoperative evaluation of liver function in cirrhotic patients, to prevent postoperative liver failure, is very important. Sixteen patients with hepatocellular carcinoma in cirrhotic livers were enrolled in this study. Liver function was determined quantitatively by monoethylglycinexylidide (MEGX) formation from the metabolism of lidocaine. The whole liver volume and tumor volume were measured by computed tomographic volumetry. The volume of resected liver was recorded by water displacement. The relationship between liver function and remnant liver volume was determined. A relationship between the percentage remnant liver volume and ratio of MEGX formation after hepatectomy was found. The regression equation was: (postoperative MEGX formation/preoperative MEGX formation) x 100% = (0.688 x percentage remnant liver volume + 0.179) x 100% (r (2) = 0.49). A relationship between MEGX formation after hepatectomy and the international ratio (INR) of prothrombin time was also found. The regression equation was INR = 1.99 - 0.01 x MEGX (r (2) = 0.30). Post-hepatectomy liver function can be estimated for an individual patient by the appropriate regression equations. Prevention of post-hepatectomy liver failure for patients with cirrhotic livers is feasible.

Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function

This study was designed (1) to evaluate the effect of a cytochrome P450 (CYP) 1A2 inhibitor, fluvoxamine, on the pharmacokinetics of intravenous lidocaine and its 2 pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), to confirm recent in vitro results indicating that CYP1A2 is the main isoform responsible for lidocaine biotransformation and (2) to assess whether liver function has any influence on the fluvoxamine-lidocaine interaction. The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild (Child grade A) and 10 with severe (Child grade C) liver dysfunction, according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 6 days; in the other phase they received 50 mg fluvoxamine for 2 days and 100 mg fluvoxamine for the next 4 days. On day 6, a 1-mg/kg lidocaine dose was administered intravenously 2 hours after the last dose of fluvoxamine or placebo. Plasma concentrations of lidocaine, MEGX, GX, and fluvoxamine were measured up to 12 hours after lidocaine injection. The effects of fluvoxamine coadministration were dependent on liver function. Lidocaine clearance was decreased on average by 60% (from 12.1 mL/min.kg to 4.85 mL/min.kg, P <.001) in healthy subjects and by 44% (from 9.83 mL/min.kg to 5.06 mL/min.kg, P <.001) in patients with mild liver dysfunction, with proportional increases in terminal half-lives, whereas virtually no effect was produced in patients with severe liver dysfunction (4.21 mL/min.kg versus 3.65 mL/min.kg, P >.05). Analogous effects were observed on MEGX and GX formation kinetics, which were drastically impaired in healthy subjects and patients with mild liver cirrhosis but virtually unaffected in patients with severe cirrhosis. CYP1A2 is the enzyme principally responsible for the metabolic disposition of lidocaine in subjects with normal liver function. The extent of fluvoxamine-lidocaine interaction decreases as liver function worsens, most likely because of the concomitant decrease in the hepatic level of CYP1A2. These observations indicate that results obtained in healthy subjects cannot be extended a priori to patients with liver dysfunction, but the clinical consequences of inhibition of drug metabolism must also be assessed in such patients.

N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report.

N-acetylcysteine (NAC) has been shown to improve splanchnic blood flow in experimental studies. This report evaluates the effects of NAC on liver perfusion and lactate signal intensities in the liver tissue of septic shock patients using proton magnetic resonance imaging and spectroscopy. Furthermore, the monoethylglycinexylidide (MEGX) test was used to investigate hepatic function. Five septic shock patients received 150 mg/kg body weight NAC as an intravenous bolus injection over 15 min. Lidocaine was injected both prior to and following NAC administration in order to determine MEGX formation. Measurements (hemodynamics, oxygen transport-related variables, blood samples for lactate, liver-related markers) were performed 1 hour before and 1 hour after NAC injection. In addition to the proton magnetic resonance imaging patients received two proton magnetic resonance spectra, one prior to and one 30 min subsequent to the onset of the NAC infusion at a 1.5 Tesla clinical scanner, for measurement of liver perfusion and liver lactate signal intensity. Following NAC infusion, the lactate signal intensity in the liver tissue showed a median decrease of 89% (11-99%), there was a median increase in liver perfusion of 41% (-14 to 559%), and the MEGX serum concentration increased three times (1.52-5.91). A decrease in the lactate signal intensity in the liver tissue and an increase in the MEGX serum concentration and in liver perfusion might indicate improved liver function as a result of NAC administration. Patients with compromised hepatosplanchnic function, such as patients with septic shock due to peritonitis, may therefore benefit from NAC therapy.

Reassessment of monoethylglycinexylidide as preoperative liver function test in a rat model of liver cirrhosis and man.

Liver cirrhosis was produced in rats by intra-abdominal injection of thioacetamide. MEGX, indocyanine green test (ICG), and liver biochemical variables were measured periodically. Then, survival rates were assessed after the rats received a 70% hepatectomy. MEGX levels were measured in various human patients with chronic hepatitis or liver cirrhosis who underwent hepatectomy. Serum MEGX levels significantly dropped and ICG levels significantly rose with macroscopic and histologic progression of liver cirrhosis in rats. The MEGX levels correlated closely with albumin levels and ICG. Preoperative MEGX and ICG levels of the mortal group of rats differed significantly from those of the survival group with 70% hepatectomy. Furthermore, 100% of the rats with MEGX levels above 40 ng/ml and ICG levels below 1.0%. In the clinical study, MEGX levels were significantly lower in patients with chronic hepatitis or liver cirrhosis than in healthy volunteers and correlated significantly with liver function tests such as albumin, Fischer's ratio, prothrombin time, hepaplastin and ICG. A significant difference was found in MEGX levels between patients receiving lobectomy and those receiving subsegmentectomy or partial hepatectomy. All patients tolerated their operations. Our data indicate that the MEGX test combined with ICG test and Child-Pugh classification is a better predictor of residual liver reserve capacity, and the analysis of hepatic MEGX formation might prove useful for rapid and reliable assessment liver function and choice of surgical treatment.

A preliminary evaluation of the discriminative power of the monoethylglycinexylidide formation test after intravenous and oral administration of lidocaine

A preliminary evaluation of the discriminative power of the monoethylglycinexylidide formation test after intravenous and oral administration of lidocaine

Assessment of hepatic function in cystic fibrosis by lidocaine metabolism.

To determine hepatic drug metabolism in patients with cystic fibrosis, as measured by monoethylglycinexylidide formation after lidocaine injection and indocyanine green (ICG) clearance. The following study is a case-control study, which included 19 patients with cystic fibrosis and 13 control subjects. Serum monoethylglycinexylidide concentration was measured after intravenous injection of 1 mg/kg (maximum, 50 mg) lidocaine. Indocyanine green (0.5 mg/kg) was injected concomitantly, and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. Monoethylglycinexylidide formation was decreased in patients with cystic fibrosis compared with controls (39.4+/-16.9 microg/L versus 70.3+/-45.7 microg/L, mean +/- SD, respectively, P < 0.02). Indocyanine green half-life (4.6+/-2.7 min versus 3.0+/-1.0 min), volume of distribution (8.6+/-5.5 L versus 8.3+/-3.4 L), and hepatic blood flow (10.9+/-5.9 ml x kg(-1) x min(-1) versus 7.4+/-2.0 ml x kg(-1) x min(-1)) were similar in both groups. Monoethylglycinexylidide formation after lidocaine injection is impaired in patients with cystic fibrosis. This impairment may have clinical implications when using hepatically metabolized medications in patients with cystic fibrosis.

Assessment of Hepatic Function in Cystic Fibrosis by Lidocaine Metabolism

ABSTRACTBackgroundTo determine hepatic drug metabolism in patients with cystic fibrosis, as measured by monoethylglycinexylidide formation after lidocaine injection and indocyanine green (ICG) clearance.MethodsThe following study is a case–control study, which included 19 patients with cystic fibrosis and 13 control subjects. Serum monoethylglycinexylidide concentration was measured after intravenous injection of 1 mg/kg (maximum, 50 mg) lidocaine. Indocyanine green (0.5 mg/kg) was injected concomitantly, and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half‐life, and hepatic blood flow.ResultsMonoethylglycinexylidide formation was decreased in patients with cystic fibrosis compared with controls (39.4 ± 16.9 μg/L versus 70.3 ± 45.7 μg/L, mean ± SD , respectively, P &lt; 0.02). Indocyanine green half‐life (4.6 ± 2.7 min versus 3.0 ± 1.0 min), volume of distribution (8.6 ± 5.5 L versus 8.3 ± 3.4 L), and hepatic blood flow (10.9 ± 5.9 ml · kg−1 · min−1 versus 7.4 ± 2.0 ml · kg−1 · min−1) were similar in both groups.ConclusionMonoethylglycinexylidide formation after lidocaine injection is impaired in patients with cystic fibrosis. This impairment may have clinical implications when using hepatically metabolized medications in patients with cystic fibrosis.

Effects of Chronic Renal Failure and Hemodialysis on the Monoethylglycinexylidide Liver Function Test

Monoethylglycinexylidide (MEGX), the primary metabolite of lidocaine, is produced via oxidative N-deethylation catalyzed by cytochrome P450 (CYP) 3A4 (1). The MEGX test, a new dynamic test of liver function that assesses the rate of MEGX formation after a standard intravenous dose of lidocaine, is a highly sensitive indicator of hepatic dysfunction and has gained the widest acceptance among dynamic liver function tests, especially in the field of liver transplantation (2). Although various observations have provided evidence of impaired drug metabolism in patients with renal insufficiency (3), the effect of renal function on MEGX formation rate has received limited attention. The only study comparing uremic patients with healthy subjects found no statistically significant differences in MEGX values between the two study groups (4). However, in this investigation, only patients with moderate kidney dysfunction were examined and MEGX was measured only 15 min after lidocaine injection. Although this was the sampling time originally suggested by Oellerich et al. (5), these authors later observed a lesser variability in MEGX concentrations at 30 min and proposed that blood be sampled at this time for MEGX determination (6). We have shown that the intersubject variability in MEGX decreases up to 1 h in both healthy individuals and cirrhotic patients; consequently, the efficiency of the test becomes maximal when blood is sampled 60 min after lidocaine injection (7). This result was confirmed in subsequent studies (8)(9)(10). The aim of the present study was to reassess the effect of chronic renal failure on the results of the MEGX test. We studied 48 Caucasian men with informed written consent. The study protocol was approved by the local Ethics Committee. The subjects were divided into four groups on the basis of creatinine clearance (CLCR) values: Group 1, with CLCR >80 mL/min per 1.73 …

Serum leptin levels in patients with viral chronic hepatitis or liver cirrhosis

Background/Aim: Serum levels of leptin, the adipocyte-derived hormone regulating food intake and energy expenditure in mammals, have been found to be increased in cirrhotic patients. The aim of the present study was to investigate leptin serum level in relation to anthropometric features and liver function in patients with viral chronic hepatitis or liver cirrhosis. Methods: Serum leptin levels were determined by radioimmunoassay in 30 male and 10 female patients with chronic hepatitis, in 42 male and 10 female patients with liver cirrhosis, and in four respective control groups. Liver function was evaluated by the monoethylglycinexylidide formation test. Body mass index and body fat mass were estimated by weight, height and skinfold thickness measurements. Results: Compared with controls, absolute serum leptin levels were significantly ( p<0.01) lower in chronic hepatitis patients and similar in cirrhotic patients. Leptin serum levels were significantly ( p<0.05) higher in cirrhotic than in chronic hepatitis patients. When expressed in relation to body fat mass, the above differences persisted; however, cirrhotic females showed significantly ( p<0;0.05) higher serum leptin values than controls. Serum leptin values correlated negatively ( p<0;0.01) with monoethylglycinexylidide serum values in all groups of patients. Conclusions: In patients with chronic viral liver disease, serum leptin levels tend to increase as liver function worsens. This may reflect a decline in the ability to downregulate energy expenditure as an adaptation to anorexia and/or to defective substrate utilisation due to liver disease and may negatively influence body weight homeostasis in these patients.

Assessment of liver function by the MEGX test in patients with schistosomiasis and cirrhosis

Objectives: The aim of this study was to determine the effect of schistosomiasis infection on hepatic function in Egyptian patients with posthepatitic cirrhosis. Design and Methods: Hepatic function, was assessed in 66 Egyptian patients, with (n = 30) and without ( n = 36) schistosomal liver fibrosis due to Schistosoma mansoni and in 20 healthy controls, using the monoethylglycinexylidide (MEGX) test. Serum MEGX concentrations were measured before and 5, 15, 30, 60, 120, and 180 min after a lidocaine bolus. The sero-prevalence of antibodies to hepatitis C was also determined in the patients. Results: MEGX test results were significantly lower in patients than in controls at all time points. MEGX test results declined with advancing Child Class. Receiver operating characteristic (ROC) curve analysis revealed the following areas under the ROC curves for discrimination of Child Class C from Child Classes A/B: 30 min, 0.762; 60 min, 0.743; 120 min, 0.731; 15 min, 0.728; 180 min, 0.728; 5 min, 0.602. Schistosomiasis infection had no influence on MEGX test results when cirrhotic patients with (Schisto+) and without (Schisto−) schistosomiasis were compared. While the prevalence of the hepatitis B surface antigen was only 16.7% (Schisto−) and 26.7% (Schisto+), there was an extremely high sero-prevalence of antibodies to hepatitis C (HCV) in both groups: 88.9% (Schisto−) and 73.3% (Schisto+). Conclusions: The association of schistosomal liver fibrosis with cirrhosis does not additionally influence MEGX formation. In addition, HCV rather than schistosomiasis infection must be considered as a major cause for the progressive liver disease in these patients.

Progressive liver functional impairment is associated with an increase in AST/ALT ratio.

The ratio of serum aspartate aminotransferase to alanine aminotransferase (AST/ALT ratio) has been proposed as a noninvasive method of assessing liver fibrosis and cirrhosis. Our aims were to confirm the usefulness of the AST/ALT ratio in diagnosing cirrhosis noninvasively as well as to verify the existence of a relationship between the ratio and liver functional impairment. In all, 348 patients (177 with chronic hepatitis, 171 with cirrhosis) were retrospectively evaluated and the AST/ALT ratio was related to monoethyl glycine xylidide (MEGX) formation. Moreover, in a subgroup of 54 patients we analyzed the relationships among the AST/ALT ratio and indocyanine green clearance and half-life. The AST/ALT ratio was able to separate patients with mild fibrosis from those with severe fibrosis and cirrhosis. The AST/ALT ratio, MEGX, prothrombin activity, and platelet count were selected by multivariate analysis as variables associated with cirrhosis. The AST/ALT ratio showed significant correlations both with MEGX formation and with indocyanine green clearance and half-life. The alterations of indocyanine green kinetics, which depend upon liver blood flow and uptake, were likely due to progressive fibrosis. These findings might partially explain the increase in the AST/ALT ratio as disease progresses.

The monoethylglycinexylidide test for grading of liver cirrhosis.

Monoethylglycinexylidide (MEGX) formation following lignocaine injection has recently been proposed as a simple dynamic liver function test based on a single measurement of its serum concentration. To determine the optimal sampling time for MEGX determination. A modelling analysis of lignocaine and MEGX kinetics was performed in seven normals and in four patients with compensated liver cirrhosis; a similar study was performed in 74 cirrhotic patients, divided into two groups according to disease severity (Pugh score). Only the MEGX fractional formation rate (kf) and formation delay (tau) were significantly altered in cirrhotic patients compared to normals: kf = 0.15 +/- 0.03 vs. 0.32 +/- 0.10 min-1 (mean +/- s.d.); tau = 7.7 +/- 2.0 vs. 3.9 +/- 2.9 min-1. A good correlation was found between kf and late (r = 0.82) but not early (r = 0.63) serum MEGX formation, suggesting that late measurements for the clinical MEGX test are preferred. In the second part of our investigation, by discriminant analysis of MEGX test data for 74 cirrhotic patients, the late MEGX concentrations gave the best discrimination between the two classes. In particular, the 60 min MEGX concentration showed the best diagnostic accuracy (81%), sensitivity (75%) and specificity (84%). The association of this with other MEGX parameters, either singly or derived from the whole curve measurements, did not improve the performance of the method. The MEGX test, based on a single determination 60 min after lignocaine injection, may be regarded as a simple and sensitive quantitative liver function test.

Capillary gas chromatographic method for the measurement of small concentrations of monoethylglycinexylidide and lidocaine in plasma

The major metabolite of lidocaine, monoethylglycinexylidide (MEGX) is currently used as a dynamic marker of liver function. It has been proven, in recent advances, that the determination of MEGX formation after intravenous injection of lidocaine was an effective means of assessing liver dysfunction in critically ill patients. An accurate and sensitive gas chromatographic method has been developed for the determination of small quantities of MEGX formed in such cases. The procedure involves a solid-phase extraction and injection of the extract (splitless mode) into a gas chromatograph equipped with a capillary column and nitrogen–phosphorus detector. The limit of detection is 1 ng/ml and the limit of quantification is 2.5 ng/ml. The response is linear up to 50 ng/ml. The inter- and intra-assay coefficients of variation for MEGX and lidocaine are between 5 and 9%. This method can be used for the determination of small concentrations of MEGX in plasma and could be applied to analysis of small amounts of many other nitrogenous molecules.

Hepatic function as assessed by lidocaine metabolism in sickle cell disease

To evaluate hepatic drug metabolism, as determined by the formation of monoethylglycinexylidide (MEGX) after lidocaine injection and indocyanine green (ICG) clearance, in patients with sickle cell disease. A case-control study including 19 patients with homozygous hemoglobin S, and 13 age- and sex-matched black control subjects. Serum MEGX concentration was measured after intravenous injection of 1 mg/kg (maximum 50 mg) lidocaine. ICG (0.5 mg/kg) was injected concomitantly and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. MEGX formation at 15 minutes was decreased in patients with sickle cell disease compared with formation in the control subjects (39.9 +/- 18.0 vs 65.6 +/- 50.0 micrograms/L, respectively, p < 0.02). The volume of distribution of ICG was increased in patients with sickle cell disease compared with that in the control subjects (0.21 +/- 0.09 vs 0.11 +/- 0.03 L/kg, p < 0.01). This partly accounts for the decreased MEGX formation. The ICG half-life was similar in both groups (3.8 +/- 1.5 vs 3.1 +/- 1.0 min). Hepatic blood flow, derived from ICG clearance, was increased in sickle cell patients compared with that of the control subjects (12.2 +/- 4.5 vs 8.1 +/- 2.1 ml/kg/min, p < 0.01). Hepatic drug metabolism, as assessed by MEGX formation after lidocaine injection, is impaired in patients with sickle cell disease. This impairment may have clinical implications when using hepatically metabolized medications in patients with sickle cell disease.

Determination of monoethylglycinexylidide by fluorescence polarization immunoassay in highly icteric serum samples: modified precipitation procedure and HPLC compared

Hyperbilirubinemia, which frequently occurs in severe liver disease, interferes with the fluorescence polarization immunoassay (FPIA) monoethylglycinexylidide (MEGX) assay manufactured by Abbott Diagnostics. Because the MEGX test is particularly helpful in this clinical situation, strategies have been developed to overcome this problem. Precipitation of serum with the Abbott Digoxin II precipitation reagent eliminates bilirubin. Therefore, we compared FPIA results after precipitation of 81 icteric samples from 27 MEGX tests to results obtained using a validated HPLC method. The precipitation did not substantially alter the performance characteristics of FPIA: detection limit, 8 microg/L; between-days imprecision, 5.3-6.2%; recovery, 102-104% (50-200 microg/L). This pretreatment of serum did not eliminate all interference, and only a poor correlation was observed between serum MEGX concentrations measured with HPLC or modified FPIA (r2 = 0.46; S(y/x) = 20.0 microg/L). In contrast, MEGX formation values calculated by subtraction of the prelidocaine MEGX concentration were in close agreement (r2 = 0.98; S(y/x) = 2.3 microg/L). Because only MEGX formation is clinically relevant, this modified FPIA procedure offers a simple and rapid alternative to HPLC.

Monoethylglycinexylidide (MEGX) as an early predictor of liver dysfunction in severe sepsis

The present study aimed to i) assess the prognostic value of monoethylglycinexylidide (MEGX) formation kinetics in predicting liver dysfunction in patients with severe sepsis, and ii) to compare it with other oxygen indices and with gastric mucosal pH (pHi). Twenty-seven patients meeting the criteria for severe sepsis were prospectively evaluated. Patients with haemodynamic instability, elevated liver enzymes (&gt;2 × normal) and bilirubin levels (&gt;3 mg/dl), coagulation disorders and gastro-intestinal bleeding were not included. A gastric tonometer (TRIP, Tonometrics, Worcester, MA, USA) was introduced in all patients. Gastric pHi was calculated using the Henderson-Hasselbalch equation. Oxygen delivery (DO2) was calculated by the simplified formula DO2 =CI×CaO2, where CI is cardiac index and CaO2 is arterial oxygen content. Oxygen consumption (VO2) was determined by indirect calculation of the product of CI and arteriovenous oxygen content difference. Plasma aspartate aminotransferase, alanine aminotransferase, bilirubin and arterial lactate levels were determined by an enzymatic method. The serum MEGX concentrations were determined using an automated fluorescence polarisation immunoassay (TDX, Abbott, Chicago, IL, USA) before, 15 and 30 minutes after an intravenous injection of 1 mg/kg lignocaine. After recording the admission parameters, all patients were treated according to a supportive therapy protocol for severe sepsis and observed throughout their stay in the intensive care unit. Predetermined liver dysfunction indices (bil &gt;3 mg/dl, liver enzymes &gt;2 × normal) were recorded until discharge or death. The ability to predict liver dysfunction was compared by calculating the sensitivity and specificity for each variable (lactate, pHi, MEGX).To evaluate the accuracy with which these variables were able to discriminate between those patients who developed clinically demonstrable liver dysfunction (LD+) and those who did not (LD-), receiver-operating characteristic (ROC) curves were constructed. Values of the measurements given as medians were compared by the Mann-Whitney U-test. MEGX was the only parameter that showed a significant difference when comparing the two groups (LD+, LD-). In ROC curves constructed to compare the ability of the variables to discriminate between the two patient groups, MEGX displayed the greatest predictability of liver failure development compared to lactate or pHi. Relating these variables to survival, no significant values were found in any of the parameters. No correlation was found between MEGX or pHi and oxygen-derived variables (DO2, VO2). There was also no significant difference in haemodynamics and oxygen-derived variables either between LD+ and LD- groups, or between survivors and non-survivors. Our data demonstrate that MEGX formation kinetics is an early bedside procedure to assess hepatic function dynamically. This test might be an early sign of hepatic insult in sepsis despite global circulatory and splanchnic circulation indices remaining within normal ranges. More research is essential to see whether this parameter can guide therapeutic strategies for preventing liver hypoxia or metabolic impairment in the early phase of severe sepsis.

The monoethylglycinexylidide test does not correctly evaluate lidocaine metabolism after ischemic liver injury in the rat.

Although the monoethylglycinexylidide (MEGX) test defined as a single determination of MEGX plasma concentration after lidocaine injection has been proposed as a liver function test, some discrepancies appeared in assessing the quality of liver donor for transplantation as well as the severity of liver disease. The present study used a severe ischemia-reperfusion liver injury (IRI) in rat to evaluate the various factors able to influence the level of MEGX. The metabolism of lidocaine was studied on microsomes isolated from intact rats and from rats submitted to this liver injury. A significant reduction of the various pathways transforming lidocaine but also MEGX was demonstrated. Lidocaine inhibited the MEGX transformation both in intact and injured liver microsomes. In vivo, plasma MEGX concentrations, determined by high-performance liquid chromatography (HPLC), were lower in IRI than in controls up to 80 minutes after lidocaine injection but not later. By contrast, using the usual commercial fluorescence polarization immunoassay (FPIA), MEGX concentrations were paradoxically higher in IRI than in controls. Moreover, MEGX values obtained using FPIA were threefold higher in controls and ninefold higher in IRI than with HPLC. It was shown that these differences were related to the detection by FPIA of free and mainly of conjugated hydroxy-MEGX that accumulated in plasma from rats submitted to an IRI. These data emphasize the complexity of factors influencing the appearance and disappearance of MEGX because of delayed MEGX formation with liver injury but also to inhibition of its further metabolization. The choice of the sampling time for MEGX determination is critical and has to be optimized in every type of liver injury. Moreover, a specific technique, such as HPLC, will avoid cross-reactivity with other metabolites, which may be particularly abundant when the biliary excretion is impaired.

The monoethylglycinexylidide test does not correctly evaluate lidocaine metabolism after ischemic liver injury in the rat

Although the monoethylglycinexylidide (MEGX) test defined as a single determination of MEGX plasma concentration after lidocaine injection has been proposed as a liver function test, some discrepancies appeared in assessing the quality of liver donor for transplantation as well as the severity of liver disease. The present study used a severe ischemia- reperfusion liver injury (IRI) in rat to evaluate the various factors able to influence the level of MEGX. The metabolism of lidocaine was studied on microsomes isolated from intact rats and from rats submitted to this liver injury. A significant reduction of the various pathways transforming lidocaine but also MEGX was demonstrated. Lidocaine inhibited the MEGX transformation both in intact and injured liver microsomes. In vivo, plasma MEGX concentrations, determined by high-performance liquid chromatography (HPLC), were lower in IRI than in controls up to 80 minutes after lidocaine injection but not later. By contrast, using the usual commercial fluorescence polarization immunoassay (FPIA), MEGX concentrations were paradoxically higher in IRI than in controls. Moreover, MEGX values obtained using FPIA were threefold higher in controls and ninefold higher in IRI than with HPLC. It was shown that these differences were related to the detection by FPIA of free and mainly of conjugated hydroxy-MEGX that accumulated in plasma from rats submitted to an IRI. These data emphasize the complexity of factors influencing the appearance and disappearance of MEGX because of delayed MEGX formation with liver injury but also to inhibition of its further metabolization. The choice of the sampling time for MEGX determination is critical and has to be optimized in every type of liver injury. Moreover, a specific technique, such as HPLC, will avoid cross-reactivity with other metabolites, which may be particularly abundant when the biliary excretion is impaired. (Hepatology 1997 Nov;26(5):1182-8)