Effect of endotoxin shock on the clearance of lidocaine and indocyanine green in the perfused rat liver.
Endotoxin administration and cecal ligation and puncture produce significant hepatocellular dysfunction when studied in vivo. Specific factors that are present in vivo after endotoxin administration and cecal ligation and puncture, such as alterations in liver blood flow, circulating mediators, and hypoxia, can alter hepatic function. In this study, we used an isolated perfused liver to evaluate the effects of in vivo administration of endotoxin on hepatic function using indocyanine green (ICG) as a global marker of function and lidocaine and its metabolite, MEGX, as specific markers of the CYP450 enzyme system. Endotoxin (Escherichia coli; 45 mg/kg i.p.) was administered to rats followed by a 6-h monitoring before preparation of the isolated in situ perfused liver. Livers from control and endotoxin groups received either ICG (control, n = 6; endotoxin, n = 5) or lidocaine (control, n = 8; endotoxin, n = 8). A separate group of rats (n = 6) received cimetidine (an inhibitor of the CYP450 enzyme system) at a dose of 80 mg/kg daily for 3 days. Livers were perfused via the portal vein by using a single-pass system with a balanced salt solution 6 h after receiving either endotoxin or saline or 24 h after receiving the last dose of cimetidine. After a 40-min stabilization period, ICG or lidocaine was infused via the portal vein until steady-state concentrations were reached in the venous outflow. The total hepatic clearance and intrinsic hepatic clearance for ICG and lidocaine were unchanged in the livers obtained from endotoxin-treated rats. This model could adequately detect CYP450 inhibition because cimetidine-treated rats had significantly lower initial MEGX concentrations (0.63 +/- 0.03 mg/L) compared with control (0.77 +/- 0.03 mg/L) and endotoxin-treated (0.74 +/- 0.04 mg/L) rats. Septic livers had significantly higher initial hepatic oxygen consumption (HVO2) than did control livers (45 +/- 3 microL/min/g vs 82 +/- 9 microL/min/g). The HVO2 remained higher in the septic livers and significantly increased throughout the study, which demonstrated that the livers remained viable and functional. These data indicate that there is no detectable hepatocellular dysfunction after endotoxin shock using ICG, lidocaine, and MEGX in the isolated perfused liver; therefore the dysfunction reported from in vivo studies may be reversible when the liver is removed from the shocked environment.
McKindley
D S
DS
University of Rhode Island, College of Pharmacy, Kingston 02881, USA.
Chichester
C
C
Raymond
R
R
D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D004396:Coloring Agents / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007208:Indocyanine Green / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008012:Lidocaine / Q000031:analogs & derivatives / Q000032:analysis / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010101:Oxygen Consumption; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000378:metabolism*
D000779:Anesthetics, Local; D004396:Coloring Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; C001173:monoethylglycinexylidide; D007208:Indocyanine Green