RT Journal Article
SR Electronic
T1 In vivo glucuronidation in rat and humans of 5,6-dihydro-7-(1H-imidazol-1-yl)-naphthalene-2-carboxylic acid, a selective inhibitor of thromboxane synthase.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 151
OP 155
VO 21
IS 1
A1 J Thomassin
A1 R Battaglia
A1 C Allievi
A1 M G Castelli
A1 M Strolin Benedetti
YR 1993
UL http://dmd.aspetjournals.org/content/21/1/151.abstract
AB The metabolites of 5,6-dihydro-7-(1H-imidazol-1-yl)-naphthalene-2-carboxylic acid, FCE 22178, a new thromboxane synthase inhibitor, were investigated in urine of rats and healthy volunteers after a single oral dose of 10 mg/kg and 400 mg, respectively, of the tritium-labeled drug. Cumulative urinary excretion of radioactivity after 4 days amounted to 64.6% and 91.0% of the dose in rat and humans, respectively. Urinary fractions of 0-24 hr, accounting for 61.8% and 79.5% of the dose, were analyzed by radio-HPLC with direct injection. Following incubation with beta-glucuronidase both in the presence and absence of saccharo-1,4-beta-lactone, a specific inhibitor of this enzyme, a metabolite was identified as a glucuronoconjugate of FCE 22178. The recovery of the glucuronide in the rat and man amounted to approximately 30% and almost 100% of urinary radioactivity, respectively. Control incubations showed a complete deglucuronidation in the case of rat urine compared with less than 10% in human urine. Addition of saccharo-1,4-beta-lactone abolished this phenomenon, suggesting the presence of an endogenous beta-glucuronidase in rat urine. Further identification of the only metabolite present in human urine by tandem MS analysis confirmed the structure of the acyl glucuronide of FCE 22178.