Leukotriene C4 disposition and metabolism in the anesthetized and endotoxemic dog.
The metabolism and disposition of tritiated leukotriene C4, [3H]-LTC4, were studied in control dogs and endotoxin-treated dogs. Radioactivity was monitored in plasma, bile, and urine for 4.5 hr after an IV bolus of [3H]-LTC4. A decreased recovery of radioactivity in bile and urine was observed in the endotoxin-treated dogs. Cumulative [3H]-LTC4 metabolic patterns in bile and urine were determined by reverse-phase high-performance liquid chromatography (RP-HPLC) separation. Three primary metabolites, [3H]-LTD4, [3H]-LTE4, and a polar metabolite, (0.15-0.19)LT, accounted for most of the total bile radioactivity. The same primary metabolites were found for endotoxin-treated dogs and in similar relative amounts. [3H]-LTE4 and the polar metabolite (0.15-0.21)LT were the primary metabolites found in urine, but no N-acetyl LTE4 was found in bile or urine for either group. Plasma incubation of [3H]-LTC4 revealed heat-sensitive dipeptidase and glutamyl transpeptidase activity with significant production of [3H]-LTD4 and [3H]-LTE4 after 5- and 30-min incubation. Pharmacokinetic analysis using the two-compartment open model revealed an increased distribution phase rate constant (alpha) and distribution phase half-life [t1/2(alpha)], and decreased clearance (ClB), volume of distribution [Vd(ss) and Vd(area)] and elimination rate microconstant (Kel) of tritiated leukotrienes for endotoxin-treated dogs. This analysis along with the maintained higher plasma levels of tritiated leukotrienes, [3H]-LTs, in endotoxin-treated dogs suggests that endotoxin caused a decreased body clearance and less peripheral tissue penetration of [3H]-LTs. Collectively, these results indicate that the metabolism of LTC4 to LTD4 and LTE4, but not N-acetyl LTE4, in dogs was similar to that reported for man, pig, and monkey but dissimilar to rat. Endotoxin did not affect the types or relative amounts of metabolites found in bile or urine but appears to affect the disposition of [3H]-LTs by decreasing clearance and distribution.
Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47905.
C A
CA
Pfeifer
G D
GD
Bottoms
M A
MA
Johnson
J
J
Fessler
D000758:Anesthesia; D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004150:Dipeptidases / Q000097:blood; D004285:Dogs; D004926:Escherichia coli; D006207:Half-Life; D007700:Kinetics; D017999:Leukotriene E4; D008297:Male; D008657:Metabolic Clearance Rate; D010396:Penicillamine / Q000494:pharmacology; D013189:SRS-A / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D012772:Shock, Septic / Q000378:metabolism*; D014316:Tritium; D005723:gamma-Glutamyltransferase / Q000097:blood
D013189:SRS-A; D014316:Tritium; D017999:Leukotriene E4; D005723:gamma-Glutamyltransferase; D004150:Dipeptidases; C038937:dipeptidase; D010396:Penicillamine