Formation route of sulfur-containing metabolites of afloqualone, a new centrally acting muscle relaxant, in rat.

Abstract

The formation route of the sulfur-containing metabolites of afloqualone [6-amino-2-fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone, AFQ], a centrally acting muscle relaxant, was studied in rats. When 14C-N-acetyl AFQ 2-mercapturate (AFQM) methyl ester was administered orally to normal rats, it was excreted in the bile as AFQM, one of the major biliary metabolites of AFQ, and in the urine as sulfur-containing metabolites of AFQ such as methylsulfinyl and methylsulfonyl metabolites of AFQ. This indicated that AFQM was a precursor of these methylsulfinyl and -sulfonyl metabolites. Pretreatment of rats with antibiotics significantly reduced the urinary excretion of 14C-AFQM and its metabolites as compared with normal rats. Oral administration of 14C-AFQ to antibiotics-treated rats also significantly reduced the amounts of the sulfur-containing metabolites excreted into the urine, but did not affect the amounts of other non-sulfur-containing metabolites. In addition, oral administration of 14C-AFQ to bile-duct-ligated rats gave results similar to those in the antibiotics-treated rats. These results indicate that in normal rats microfloral metabolism is necessary for the formation of the methylsulfinyl and -sulfonyl metabolites from AFQM and other unidentified mercapturate pathway conjugates excreted into the bile. The metabolites of AFQ produced by the microflora are reabsorbed into the systemic circulation, processed by further metabolism in the liver, and in turn excreted in the urine.