Metabolic formation of N- and O-glucuronides of 3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid. Rearrangement of the 1-o-acyl glucuronide.
Excretion of 3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid (I) and its metabolites was studied in rats, beagle dogs, and rhesus monkeys given 20-mg/kg doses of 14C-labeled drug. The urine of rhesus monkeys contained two metabolites in addition to unchanged drug. Both metabolites were hydrolyzed to I by beta-glucuronidase and the hydrolysis was inhibited by 1,4-saccharolactone, indicating that they were glucuronides of I. One of the metabolites (III) was not hydrolyzed by dilute alkali. Its NMR spectrum indicated that the site of conjugation was one of the nitrogen atoms, i.e., it was a quaternary N-glucuronide. The FAB mass spectrum was in conformity with this assignment. This metabolite was not present in the urine of dogs or rats given labeled drug. The other metabolite (II) was excreted in the urine of all three species as well as in the bile of the rat. It was readily hydrolyzed by dilute alkali (pH 11 for 0.5 hr at 37 degrees C), indicating that this metabolite was an acyl glucuronide. The metabolite was stable at pH 4.5 but it was readily converted to three isomers at 37 degrees C within 1 hr at pH 6.5 and above. The mass spectra of the derivatized isomers and metabolite were similar. The isomers were hydrolyzed to I by dilute alkali but not by beta-glucuronidase. They exhibited reducing properties (whereas metabolite II did not), suggesting that they were formed by acyl migration of the aglycone to the second, third, and fourth carbon atoms of the glucuronic acid moiety. Acyl migration probably plays a role in the disposition of I as well as other drugs that form labile glucuronides.
D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism* / Q000652:urine; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005965:Glucuronates / Q000302:isolation & purification / Q000378:metabolism; D006868:Hydrolysis; D007536:Isomerism; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats
D001562:Benzimidazoles; D005965:Glucuronates; C029171:tilomisole