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

Abstract

Although the monoethylglycinexylidide (MEGX) test de-activity of various cytochrome P-450 enzymes. [1][2][3] For clinical fined as a single determination of MEGX plasma concentra-application, the time-consuming repetitive determinations, tion after lidocaine injection has been proposed as a liver usually by high-performance liquid chromatography (HPLC) function test, some discrepancies appeared in assessing the of lidocaine plasma concentrations, were replaced by a single quality of liver donor for transplantation as well as the severity point measurement of one of its metabolites, the monoethylof liver disease. The present study used a severe ischemia-glycinexilidide (MEGX) with a convenient fluorescence poreperfusion liver injury (IRI) in rat to evaluate the various larization immunoassay (FPIA). 4 This test found many applifactors able to influence the level of MEGX. The metabolism cations in adult and pediatric hepatology [5][6][7][8][9][10] ; however, its of lidocaine was studied on microsomes isolated from intact initial relevance in the evaluation of organ viability before rats and from rats submitted to this liver injury. A significant transplantation has not been confirmed by subsequent studreduction of the various pathways transforming lidocaine but ies. 3,[11][12][13] In a preliminary study, we also observed that in a also MEGX was demonstrated. Lidocaine inhibited the MEGX well-defined model of severe liver injury produced in rat by transformation both in intact and injured liver microsomes. a period of ischemia followed by reperfusion, paradoxical In vivo, plasma MEGX concentrations, determined by high-results were obtained as MEGX value above the normal was performance liquid chromatography (HPLC), were lower in concomitant with a lethal injury within the next 24 hours. 14 IRI than in controls up to 80 minutes after lidocaine injection Although there are some differences in lidocaine metabolism but not later. By contrast, using the usual commercial fluores-between rat and man, 15 this model of liver injury could be cence polarization immunoassay (FPIA), MEGX concentra-used to critically test two assumptions about the MEGX test tions were paradoxically higher in IRI than in controls. More-that have not been confirmed experimentally. The first one over, MEGX values obtained using FPIA were threefold higher is that the determination of MEGX concentration at a single in controls and ninefold higher in IRI than with HPLC. It was time point is a reliable index of the lidocaine metabolism. shown that these differences were related to the detection by This could probably be questioned, because MEGX is only FPIA of free and mainly of conjugated hydroxy-MEGX that one of the metabolites of lidocaine and is itself submitted accumulated in plasma from rats submitted to an IRI. These to further transformations. Indeed, in humans, lidocaine is data emphasize the complexity of factors influencing the ap-mainly deethylated to MEGX and is, to a lesser extent, hypearance and disappearance of MEGX because of delayed d...