Mexiletine carbonyloxy beta-D-glucuronide: a novel metabolite in human urine.
1. The study was performed to isolate and characterize a glucuronic acid conjugate of mexiletine that releases mexiletine on acid hydrolysis from urine samples obtained from healthy volunteers following a single oral dose of mexiletine. 2. The [M-H]- ion of the isolated metabolite was observed at m/z 398 in the negative electrospray ionization mass spectrum. This mass number was 44 higher than that of the product generated when mexiletine is subjected to direct glucuronidation. In positive-ion mode, collision-induced dissociation of the quasimolecular ion [M+NH4]+, m/z 417, gave product ions at m/z 224, 180 and 58. These mass spectral data indicated that the metabolite contained a carbonyloxy moiety in its structure in addition to mexiletine and a glucuronic acid moiety. 3. The presence of this carbonyloxy moiety was further supported by the following chemical reactions. When the metabolite was hydrolysed with an aqueous solution of 1 M sodium hydroxide at room temperature, mexiletine was released, whereas the N-methoxycarbonyl derivative of mexiletine was obtained after treatment of the metabolite with methanolic sodium hydroxide solution. 4. The results indicated that the structure of the isolated metabolite was the N-carbonyloxy beta-D-glucuronic acid conjugate of mexiletine.
Senda
C
C
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Toda
S
S
Tateishi
M
M
Kobayashi
K
K
Igarashi
T
T
Chiba
K
K
D000328:Adult; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism* / Q000652:urine*; D006801:Humans; D006868:Hydrolysis; D008297:Male; D013058:Mass Spectrometry; D008801:Mexiletine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000652:urine*; D015394:Molecular Structure
D020719:Glucuronides; C486473:mexiletine carbonyloxy glucuronide; D008801:Mexiletine