Metabolism of N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide (S-23121) in the rat: I. Identification of a new, sulphonic acid type of conjugate

Abstract

1. Several metabolites of ¹⁴C-labelled N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetra-hydrophthalimide (S-23121) were identified.

2. The major urinary metabolites were found to be 4-chloro-2-fluoro-5-hydroxyaniline, its sulphate and glucuronide by t.l.c. cochromatography with authentic standards.

3. The major faecal metabolites in addition to the parent compound were six sulphonic acid conjugates having a sulphonic acid group incorporated into the double bond of the 3,4,5,6-tetrahydrophthalimide moiety. These sulphonic acid conjugates have never been reported previously for this type of compound.

4. To confirm the mechanism of biosynthesis of the sulphonic acid conjugates, sodium sulphate, cysteine and glutathione labelled with ³⁵S were administered to the male rat together with unlabelled S-23121. The same faecal metabolites as those detected in faeces of the rat dosed with ¹⁴C-labelled S-23121 were similarly found after dosing with any of the ³⁵S-labelled chemicals. Their biosynthesis was most pronounced with ³⁵S-labeiled sodium sulphate, implying that the sulphonic acid is incorporated into the double bond after reduction of sulphate to sulphite.