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

Abstract

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 β-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 (176amu) 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 pH5 as is often the case with N-glucuronides of arylamines. M₃G could be hydrolysed by β-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.