Significant hepatic dysfunction occurs following
endotoxin administration. Although the metabolism of
lidocaine to one of the primary metabolites of
lidocaine,
monoethylglycinexylidide (
MEGX), has been used as a marker of hepatic function under various conditions, it remains unknown whether these compounds can be used in vivo to evaluate hepatic function in a rat model of endotoxic
shock. To study this,
cytochrome P450-3A4 (
CYP3A4) was determined after harvesting hepatic microsomes, hepatic blood flow was determined using radioactive
microspheres, and the pharmacokinetics of
lidocaine and
MEGX were evaluated. Adult male Sprague-Dawley rats were divided into
endotoxin (45 mg/kg, intraperitoneally; n = 28) or control (n = 32) groups. The
CYP3A4 was significantly reduced after endotoxic
shock.
Carboxylesterase (
hydrolase S) content, which was used as a control for microsomal
protein, was not significantly different between groups. Total hepatic blood flow was significantly decreased (36.2 +/- 8.4 mL/min/100 g tissue vs. 120.4 +/- 10.6 mL/min/100 g tissue), which was due to the decreased portal blood flow. For the
lidocaine and
MEGX experiment,
lidocaine (2 mg/kg) was administered followed by serial blood samples collected up to 2 h for determination of serum
lidocaine and
MEGX concentrations. Mean arterial pressure (MAP) was recorded throughout the experiment. The MAP was significantly lower in the
endotoxin treated rats vs. control 7.5 to 8 h following
endotoxin administration. Serum concentrations of
lidocaine were higher in endotoxic
shock versus control animals at 2 h following
lidocaine administration (1.5 +/- 0.13 mg/L vs. 0.11 +/- 0.03 mg/L). Similarly,
MEGX concentrations were significantly higher in endotoxic
shock versus control animals (0.55 +/- 0.04 mg/L vs. 0.16 +/- 0.02, respectively) under such conditions. These data demonstrate that the elimination of
lidocaine and
MEGX is impaired during endotoxic
shock. The elevated
lidocaine and
MEGX concentrations are likely to be the result of primarily reduced hepatic blood flow and secondarily due to impaired CYP450, one of which was
CYP3A4. The reduced elimination of
MEGX concentrations is not due to decreased hepatic metabolism of the compound via
carboxylesterase. The ratio of
MEGX to
lidocaine concentrations, which decreased significantly following endotoxic
shock, appears to be a useful measure of hepatic function during endotoxic
shock where profound reductions of hepatic blood flow are observed in addition to significant reductions in CYP450. The use of only
MEGX concentrations in this endotoxic
shock model is not useful in evaluating liver function.