Metabolism and excretion of exogenous ( sup 3 H)-LTC4 in primates

Journal Article · Thu Jun 01 04:00:00 EDT 1989 · Prostaglandins; (USA)

DOI:https://doi.org/10.1016/0090-6980(89)90101-9· OSTI ID:5412053

Tagari, P; Foster, A; Delorme, D; Girard, Y; Rokach, J ^[1]

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1. Merck Frosst Canada Inc., Dorval, Quebec

Four novel omega- and beta-oxidation (from the omega end) products of peptide leukotrienes, 20-hydroxy and 20-carboxy-LTE4, 18-carboxy-19, 20-dinor-LTE4 and 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-LTE4 were prepared by total synthesis and used as standards for identification of biliary and urinary metabolites in the cynomolgus monkey. After intravenous administration 14, 15-(3H) leukotriene C4 (10 microCi kg-1) was partially metabolized in and rapidly cleared from the vascular circulation. This resulted, within 24 hours, in significant urinary excretion (14.8 +/- 2.1%, n = 4), consisting largely of material more polar than LTE4 (61% of urinary excretion) as shown by reverse phase HPLC. The polar fraction demonstrated two predominant metabolites which coeluted in several HPLC solvent systems with synthetic 16-carboxytetranordihydro-LTE4 (major component) and 18-carboxydinor-LTE4 (minor component). Characterization of the major polar metabolite as 16-carboxytetranordihydro-LTE4 was substantiated by conversion to its N-acetylated derivative. The absence of the 14, 15 double bond was confirmed by product analysis of oxidative ozonolysis. In a single animal, the bile duct was cannulated, with significant biliary excretion of radioactivity demonstrated over 4 hours (58.6% recovery). The predominant polar biliary metabolites were also identified as the 18-carboxydinor and 16-carboxytetranordihydro derivatives of LTE4 mentioned above. These data suggest that beta-oxidation products generated from the omega-carboxyl end of the 20-carboxy-LTE4 are important products of (3H) LTC4 metabolism in the monkey. Quantitation of these urinary metabolites may be an important index of in vivo leukotriene production.

• OSTI ID: 5412053
• Journal Information: Prostaglandins; (USA), Journal Name: Prostaglandins; (USA) Vol. 37:6; ISSN PRGLB; ISSN 0090-6980
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BILE
BIOLOGICAL MATERIALS
BODY FLUIDS
CHROMATOGRAPHY
CLEARANCE
EXCRETION
HYDROGEN COMPOUNDS
INJECTION
INTAKE
INTRAVENOUS INJECTION
ISOTOPE APPLICATIONS
LIQUID COLUMN CHROMATOGRAPHY
MAMMALS
MATERIALS
METABOLISM
METABOLITES
MONKEYS
PRIMATES
PROSTAGLANDINS
SEPARATION PROCESSES
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES