Metabolism of a tetrahydroaminoacridine derivative (SM-10888) in rat: structural analysis of an N-glucuronide of SM-10888 and an O-glucuronide of hydroxylated SM-10888 by FAB-MS/MS.
1. The metabolism of 9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate (SM-10888), a cholinesterase inhibitor was studied in rat. 2. The phase I metabolite (designated M3) was isolated from urine and identified as 1-hydroxylated SM-10888 by 1H-n.m.r. and EI-MS. 3. Two glucuronides (designated SMG and M3G) were isolated from bile and urine and their structures examined by FAB-MS/MS and beta-glucuronidase hydrolysis. 4. FAB-mass spectra of SMG and M3G showed molecular ions ([M+H]+) at m/z 405 and 421, respectively. In their daughter spectra, fragment ions of aglycones (SM-10888 and M3), generated by the loss of glucuronic acid (176 amu) were observed. The daughter spectra of these aglycones were essentially similar to those of the corresponding synthetic standards. 5. SMG was hydrolysed non-enzymically at pH 5 as is often the case with N-glucuronides of arylamines. M3G could be hydrolysed by beta-glucuronidase but proved stable at pH 5. 6. From these results, SMG and M3G were concluded to be the N-glucuronide of SM-10888 and the O-glucuronide of M3, respectively.
Yabuki
M
M
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, Osaka, Japan.
Mine
T
T
Iba
K
K
Nakatsuka
I
I
Yoshitake
A
A
D000585:Aminacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D005965:Glucuronates / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment
D002800:Cholinesterase Inhibitors; D005965:Glucuronates; C065164:9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine; D000585:Aminacrine