title: Fractional conversion of thromboxane A2 and B2 to urinary 2,3-dinor-thromboxane B2 and 11-dehydrothromboxane B2 in the cynomolgus monkey.
abstract: Following the intravenous administration of thromboxane (TX) B2, the stable hydration product of TXA2, to human and nonhuman primates the most abundant urinary metabolites are 2,3-dinor-TXB2 and 11-dehydro-TXB2. However, it is not known whether fractional conversion of TXB2 to its enzymatic metabolites is an accurate representation of TXA2 metabolism. Thus, we have compared the metabolic disposition of synthetic TXA2 and TXB2 via the beta-oxidation and 11-OH-dehydrogenase pathways in vivo in the monkey. TXA2 or TXB2 (20 ng/kg) was intravenously administered to four cynomolgus monkeys pretreated with aspirin in order to suppress endogenous TXA2 production. Urinary TXB2, 2,3-dinor-TXB2 and 11-dehydro-TXB2 were measured before, during and up to 24 h after thromboxane administration by means of reversed-phase high-performance liquid chromatography radioimmunoassay. Aspirin treatment suppressed urinary 2,3-dinor-TXB2 and 11-dehydro-TXB2 by approx. 75%. A similar fractional conversion of TXA2 and TXB2 into 2,3-dinor-TXB2 and 11-dehydro-TXB2 was found. These results suggest that TXA2 is hydrolyzed to TXB2 prior to enzymatic degradation and that metabolites of the latter represent reliable indices of TXA2 biosynthesis. Due to the variability in the conversion of thromboxanes into 2,3-dinor-TXB2 and 11-dehydro-TXB2, the measurement of both metabolites seems to represent a more reliable index of acute changes in TXA2 production.
authors.affiliation: Merck Frosst Research Laboratories Pointe Claire-Dorval, Quebec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Patrignani
authors.forename: H
authors.initials: H
authors.lastname: Morton
authors.forename: M
authors.initials: M
authors.lastname: Cirino
authors.forename: A
authors.initials: A
authors.lastname: Lord
authors.forename: L
authors.initials: L
authors.lastname: Charette
authors.forename: J
authors.initials: J
authors.lastname: Gillard
authors.forename: J
authors.initials: J
authors.lastname: Rokach
authors.forename: C
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D011863:Radioimmunoassay; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000652:urine
chemical_list: D013929:Thromboxane B2; D013928:Thromboxane A2; C028965:2,3-dinor-thromboxane B2; C049235:11-dehydro-thromboxane B2