Endotoxic shock alters the pharmacokinetics of lidocaine and monoethylglycinexylidide.
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.
McKindley
David S
DS
Department of Pharmacy Practice, University of Rhode Island, College of Pharmacy, Kingston 02881, USA.
Boulet
Judah
J
Sachdeva
Karuna
K
Wang
Ping
P
Chichester
Clinton
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006439:Hemodynamics; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D012772:Shock, Septic / Q000503:physiopathology*
D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; C001173:monoethylglycinexylidide; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase