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.
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.
Thomassin
J
J
Department of Pharmacokinetics and Metabolism, Farmitalia Carlo Erba R&D, Milan, Italy.
Battaglia
R
R
Allievi
C
C
Castelli
M G
MG
Strolin Benedetti
M
M
D000293:Adolescent; D000328:Adult; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005965:Glucuronates; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000652:urine*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009281:Naphthalenes / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D005965:Glucuronates; D007093:Imidazoles; D009281:Naphthalenes; D005966:Glucuronidase; D013930:Thromboxane-A Synthase; C066217:rolafagrel