title: Metabolism and excretion of exogenous [3H]-LTC4 in primates.
abstract: 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.
authors.affiliation: Dept. of Pharmacology, Merck Frosst Canada Inc., Dorval, Québec.
authors.forename: P
authors.initials: P
authors.lastname: Tagari
authors.forename: A
authors.initials: A
authors.lastname: Foster
authors.forename: D
authors.initials: D
authors.lastname: Delorme
authors.forename: Y
authors.initials: Y
authors.lastname: Girard
authors.forename: J
authors.initials: J
authors.lastname: Rokach
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D017999:Leukotriene E4; D008252:Macaca fascicularis; D013189:SRS-A / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D014316:Tritium
chemical_list: D013189:SRS-A; D014316:Tritium; D017999:Leukotriene E4