Monoethylglycinexylidide Formation Research Articles

Assessment of lidocaine metabolite formation as a quantitative liver function test in children

Lidocaine, an aminoethylamide, undergoes deethylation in the liver after intravenous injection, resulting in the formation of monoethylglycinexylidide. Serum monoethylglycinexylidide concentration can be measured by a simple, rapid fluorescent polarization immunoassay. We sought to determine whether lidocaine metabolism, as indicated by monoethylglycinexylidide formation, could be used as a quantitative index of hepatic function. Therefore we measured monoethylglycinexylidide formation in 10 healthy children and in 28 children with chronic liver disease. Patients with chronic liver disease were divided by disease severity as being at low, moderate or high risk for deterioration based on a clinical scoring system for liver transplant candidates. In healthy controls, the peak monoethylglycinexylidide concentration 15 min after injection of lidocaine (1 mg/kg) was 97 +/- 12 micrograms/L (mean +/- S.E.). However, monoethylglycinexylidide concentration was decreased in 28 children with chronic liver disease (32 +/- 5 micrograms/L, p less than 0.001). Furthermore, this value was inversely proportional to the severity of liver disease. The mean difference in monoethylglycinexylidide concentration between the low-risk and high-risk groups was statistically significant (42 +/- 6 vs. 11 +/- 4 micrograms/L, respectively, p less than 0.01). We conclude that the rate of formation of the lidocaine metabolite monoethylglycinexylidide is decreased in patients with chronic liver disease and is inversely related to disease severity. Therefore measurement of monoethylglycinexylidide concentration after lidocaine injection may be used as a quantitative assessment of liver function in children. We speculate that monoethylglycinexylidide formation may be a useful prognostic index in children with liver disease.

MONOETHYLGLYCINEXYLIDIDE FORMATION: A NOVEL QUANTITATIVE LIVER FUNCTION TEST

Lidocaine is deethylated in the liver to form Monoethylglycinexylidide (MEGX) which can be measured by Fluorescent Polarization Immunoassay. In order to determine if MEGX formation can be used as a quantitative liver function test, the MEGX concentration was measured in serum 15 min after lidocaine injection (1mg/kg IV) in 15 controls and in 40 patients with chronic liver disease (CLD). Salivary MEGX concentration was measured (at 15 and 30 min) in 10 controls and in 8 pts with CLD. Serum MEGX concentration was decreased in CLD compared to controls (38 ± 5 vs 106 ± 9 μg/L, X±SE, res-pectively) in an inverse proportion to severity of CLD: low risk for death (J Ped 111 : 479) 48±6 (n=28); medium risk 27±1(n=2); high risk 13±4 (n=10). Salivary MEGX concentration was decreased in CLD compared to controls (77±19 at 15 min and 155±31 at 30 min vs 103± 7 and 346± 74, respectively, p<0.5). serum MEGX levels at 15 min correlated with salivary levels at 15 and 30 min (r=0.43 and 0.34 respectively, p<0.05).Conclusion: The serum concentration of MEGX is decreased in pts with CLD in an inverse proportion to disease severity. Salivary MEGX levels, which correlate with serum levels, are also decreased in pts with CLD. Assessment of MEGX after lidocaine injection may be a useful quantitative liver function test.

Lidocaine Metabolite Formation as a Measure of Liver Function in Patients with Cirrhosis

A method for rapid assessment of hepatic function in cirrhotics based on the formation of the lidocaine metabolite, monoethylglycinexylidide (MEGX), was evaluated. The formation kinetics and urinary excretion patterns of MEGX clearly distinguished cirrhotics (n = 12) from healthy volunteers (n = 16). In a prospective study, we compared the prognostic value of the MEGX test with that of traditional parameters in transplant candidates. Patients who underwent transplantation during follow-up were excluded. The study included 58 adult patients with biopsy-proven posthepatitic or biliary cirrhosis. During the follow-up period of 120 days, 10 of 58 patients died of their liver disease. At the time of inclusion, we recorded MEGX formation, indocyanine green (ICG) half-life, caffeine clearance, and the Child-Pugh score. These variables were subjected as covariates to a survival analysis (Cox proportional hazards regression model). The results of the MEGX and the ICG test were significantly related to the 120-day survival. In the stepwise analysis, none of the parameters evaluated contributed to a further significant improvement of our predictive ability when added to the values of ICG (improvement: p less than 0.0005) and MEGX (improvement: p less than 0.0005). These findings suggest that the ICG and MEGX tests were the best short-term prognostic indicators. The easy handling favors the MEGX test over the ICG test as a tool for assessment of hepatic function and short-term prognosis in transplant candidates with cirrhosis.

Metabolism of lidocaine by purified rat liver microsomal cytochrome P-450 isozymes

The metabolism of lidocaine was studied using rat liver microsomes or a reconstituted lidocaine monooxygenase system with one of eight forms of cytochrome P-450 purified from liver microsomes from untreated- (P450 UT-2 and UT-5), phenobarbital- (P450 PB-1, PB-2, PB-4, and PB5) or 3-methylcholanthrene- (P450 MC-1 and MC-5) treated rats. A reverse phase high-performance liquid chromatography system capable of simultaneously assaying four major lidocaine metabolites, namely, monoethylglycinexylidide (MEGX), 3-hydroxylidocaine (3-OH LID), methylhydroxylidocaine (Me-OH LID) and glycinexylidide (GX), was employed to determine the rate of formation of each metabolite. Untreated microsomes generated MEGX, Me-OH LID, and 3-OH LID, but the formation of GX was not detected. In male rat liver microsomes, MEGX was the major metabolite of lidocaine when a concentration of 1 mM was employed. The formation of MEGX and Me-OH LID was increased significantly (P < 0.01) by microsomes from phenobarbital-treated rats, and the formation of 3-OH LID was increased with 3-methylcholanthrene. The study with the reconstituted system with purified cytochrome P-450 isozymes revealed that all eight forms of cytochrome P-450 used have an ability to N-deethylate lidocaine to form MEGX. Among these isozymes, cytochrome P450 PB-4 and P450 UT2 showed a higher turnover number for the formation of MEGX. Me-OH LID was formed exclusively by P450 PB-5, and 3-OH LID exclusively by P450 MC-1. Selectivity of cytochrome P450 PB-5 for aromatic methyl hydroxylation of lidocaine was confirmed by an inhibition study; formation of Me-OH LID by microsomes of rats treated with phenobarbital was inhibited completely by antibody against P450 PB-5. It was concluded that different cytochrome P-450 isozymes metabolize lidocaine with a different rate and different position selectivities. Since a specific substrate of cytochrome P450 PB-5 (P450e) is not known, lidocaine may be a useful substrate for the identification of P450 PB-5.

Monoethylglycinexylidide formation kinetics: a novel approach to assessment of liver function.

A novel quantitative liver function test is described which is based on monoethylglycinexylidide (MEGX) formation after lidocaine bolus injection. Following the administration of small single doses of lidocaine hydrochloride (1 mg/kg), monoethylglycinexylidide serum concentration-time curves were determined by a novel highly sensitive fluorescence polarisation immunoassay (FPIA) in healthy volunteers, liver donors and patients with liver cirrhosis. The FPIA allowed rapid and reliable monoethylglycinexylidide determinations in serum and urine (between-days coefficient of variation: less than 10.3%, recovery: 80-113%). Monoethylglycinexylidide concentrations measured by FPIA in 32 serum samples from patients correlated well those determined by HPLC. The monoethylglycinexylidide concentration in serum determined 15 min after a lidocaine bolus injection proved to be a highly sensitive and specific indicator of hepatic dysfunction. Average monoethylglycinexylidide concentrations in serum obtained 15 min after lidocaine injection were substantially lower in patients with liver cirrhosis than in healthy volunteers. The average monoethylglycinexylidide concentrations in serum were also substantially lower in liver donors with ballooning or fatty changes of hepatocytes than in donors without relevant alterations of liver histology. By means of monoethylglycinexylidide formation in the liver donors, primary function of the transplanted liver was correctly predicted in 32/37 cases and initial non-function in 4/6 cases.