Assessment of canine liver function by metabolism of lidocaine to monoethylglycinexylidide: a preclinical study

Abstract

This study reports the evaluation of lidocaine pharmacokinetics and appearance and disappearance of its de-ethylated metabolite, monoethylglycinexylidide (MEGX). The study was completed to develop a new lidocaine-MEGX liver function test for use in diagnosing and monitoring dogs with chronic progressive liver disease. The lidocaine-MEGX test is used in humans for evaluation of liver function during organ transplant selection, prognostication of chronic liver disease, prioritization of liver transplant recipients, and in monitoring human patients after liver transplant. The principal of the test is that MEGX concentrations 15 or 30 minutes after lidocaine administration is representative of overall liver function. Single point assessment is possible because MEGX concentrations have a steady state plateau starting approximately 15 minutes after lidocaine administration. This plateau is preserved in patients with liver disease but occurs at lower concentrations. Alterations of lidocaine pharmacokinetics also occur in liver disease patients and have been investigated in combination with and independent of MEGX concentrations. This study examined the concentrations and pharmacokinetics of lidocaine and MEGX after administration of lidocaine at a clinically safe dose, 1 mg/kg intravenously, in eleven healthy dogs. Lidocaine and MEGX concentrations were compared using high performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) measurement of lidocaine. Measurement of lidocaine concentrations using enzyme-linked immunoassay was not successful. A MEGX concentration plateau was present in canine serum from 15 to approximately 60 minutes after lidocaine administration; however, the concentrations were only half that of humans after a comparable lidocaine dose. Lidocaine concentrations measured by HPLC and FPIA were significantly different. Concentrations obtained by FPIA were 2.5 to 4.5-fold higher than those measured by HPLC. This difference is not reported in human serum and has clinical relevance in design of a canine lidocaine-MEGX test and therapeutic drug monitoring of dogs with cardiac disease receiving lidocaine. Monoethylglycinexylidide and lidocaine measurements and pharmacokinetic calculations were hampered by limited HPLC detection ranges. Conclusions are that MEGX concentrations at 30 minutes are likely representative of the concentration plateau in dogs but that further research is necessary at a higher lidocaine dose and/or with assay methods designed for measurements of lower concentrations.