Leukotriene C4 disposition and metabolism in the anesthetized and endotoxemic dog

Journal Article · Fri Feb 01 04:00:00 EST 1991 · Circulatory Shock; (United States)

OSTI ID:5595180

Pfeifer, C A; Bottoms, G D; Johnson, M A; Fessler, J ^[1]

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1. Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Purdue University, West Lafayette, IN (USA)

The metabolism and disposition of tritiated leukotriene C4, {sup 3}H-LTC4, were studied in control dogs and endotoxin-treated dogs. Radioactivity was monitored in plasma, bile, and urine for after an IV bolus of {sup 3}H-LTC4. A decreased recovery of radioactivity in bile and urine was observed in the endotoxin-treated dogs. Cumulative {sup 3}H-LTC4 metabolic patterns in bile and urine were determined by reverse-phase high-performance liquid chromatography (RP-HPLC) separation. Three primary metabolites, {sup 3}H-LTD4, {sup 3}H-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. {sup 3}H-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 {sup 3}H-LTC4 revealed heat-sensitive dipeptidase and glutamyl transpeptidase activity with significant production of {sup 3}H-LTD4 and {sup 3}H-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, {sup 3}H-LTs, in endotoxin-treated dogs suggests that endotoxin caused a decreased body clearance and less peripheral tissue penetration of {sup 3}H-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.

• OSTI ID: 5595180
• Journal Information: Circulatory Shock; (United States), Journal Name: Circulatory Shock; (United States) Vol. 33:2; ISSN CRSHA; ISSN 0092-6213
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
ANESTHESIA
ANIMALS
ANTIGENS
BACTERIA
BILE
BIOLOGICAL HALF-LIFE
BIOLOGICAL MATERIALS
BODY FLUIDS
CARBOXYLIC ACIDS
CHELATING AGENTS
CHROMATOGRAPHY
DOGS
DRUGS
ESCHERICHIA COLI
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
LIQUID COLUMN CHROMATOGRAPHY
MAMMALS
MATERIALS
METABOLISM
METABOLITES
MICROORGANISMS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PENICILLAMINE
PROSTAGLANDINS
RADIOPROTECTIVE SUBSTANCES
SEPARATION PROCESSES
THIOLS
TOXIC MATERIALS
TOXINS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES