RT Journal Article
SR Electronic
T1 Isolation and structural characterization by spectroscopic methods of two glucuronide metabolites of mexiletine after N-oxidation and deamination.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 762
OP 769
VO 20
IS 5
A1 J Turgeon
A1 J R Paré
A1 M Lalande
A1 O Grech-Bélanger
A1 P M Bélanger
YR 1992
UL http://dmd.aspetjournals.org/content/20/5/762.abstract
AB Urine samples from control and mexiletine-treated human subjects or rabbits (test group) were collected and passed through an ion exchange resin to isolate polar compounds. Methanolic eluates from control and test urines were analyzed by TLC. Exposure to p-dimethylaminocinnamaldehyde gave an additional intense pink band at Rt 0.40-0.45 in TLC analysis of test urine eluate when compared to control urine eluate. Non-exposed silica at this Rt was scraped and metabolites were extracted with methanol. Hydrolysis of this methanolic extract at 100 degrees C with hydrochloric acid released mexiletine. GC/MS and fast atom bombardment mass spectrometry analyses of nonhydrolyzed methanolic extracts evidenced the presence of two conjugated metabolites of mexiletine, namely, N-hydroxymexiletine glucuronide and mexiletine alcohol glucuronide. Synthetic compounds corresponding to these metabolites were obtained and spectra compared with those of isolated metabolites from urine. Definite structure assignment of N-hydroxymexiletine glucuronide was obtained from NMR spectrometry which confirmed the structure to be a hydoxylamine glucuronide (N-O-C link) and showed that the glycoside moiety was in the beta configuration. Thus, it is proposed that N-hydroxymexiletine glucuronide corresponds to mexiletine acid-labile conjugate and represents a major metabolic pathway in the disposition of mexiletine.