Enzymatic hydrolysis of zenarestat 1-O-acylglucuronide.
Zenarestat, (3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-1-yl) acetic acid, an aldose reductase inhibitor is metabolized mainly to the glucuronide in rat and man. The glucuronide was purified from urine of volunteers after ingestion of zenarestat. The structure of the glucuronide was confirmed by LC-MS and NMR as 1-O-acyl-beta-glucuronide. This compound was unstable at physiological pH, being converted to its structural isomers and the aglycone with half-life of 25 min at pH 7.4 and 37 degrees C in aqueous solution. Enzymatic hydrolysis of the glucuronide was studied in urine, blood and tissues. beta-Glucuronidase in human urine contributed little to the hydrolysis of the glucuronide, while in rat urine at pH 6, it was degraded by beta-glucuronidase and the formation of zenarestat was clearly faster than its formation in buffer at pH 6. In both rat and human blood, these reactions were accelerated by albumin, although rat red blood cells may also contribute. The rate of degradation was not affected by red blood cell membrane, haemoglobin, globulin, esterases or beta-glucuronidase. Arylesterase in rat liver, arylesterase and acetylcholinesterase in the kidney, and beta-glucuronidase in both tissues may contribute. Thus, enzymatic degradation of zenarestat 1-O-acyl-beta-glucuronide is dependent not only on pH and temperature but also on species and the type of tissue or body fluid.
Product Development Laboratories, Fujisawa Pharmaceutical Co. Ltd, Osaka, Japan.
Y
Y
Tanaka
A
A
Suzuki
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005965:Glucuronates / Q000097:blood / Q000737:chemistry* / Q000652:urine; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011489:Protein Denaturation; D011799:Quinazolines / Q000097:blood / Q000737:chemistry* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D002021:Buffers; D005965:Glucuronates; D011799:Quinazolines; C064920:FR 74366; D000449:Aldehyde Reductase