Metabolism of N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide (S-23121) in the rat. II. Absorption, disposition, excretion and biotransformation

Abstract

1. To examine the metabolic fate of N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide (S-23121), rats were given a single oral dose of [phenyl-¹⁴C]S-23121 at 1 or 250mg/kg.

2. The radiocarbon was almost completely eliminated from the rat within 7 days after administration for both dose groups. Faecal ¹⁴C-excretion was major (71-86% of the dose) and urinary ¹⁴C-excretion was minor (18-30%).

3. ¹⁴C-tissue residues on the seventh day after administration were generally very low. Peak ¹⁴C-concentrations in the kidney and liver occurred 4h after administration and decreased rapidly thereafter. Amounts (percentage of dose) of the parent compound in faeces were 13-26% for low dose, and 22-35% for high dose.

4. The major metabolites in faeces were sulphonic acid conjugates (13-20% of the administered dose), formed by incorporation of a sulphonic acid group into the double bond of the tetrahydrophthalimide. The major metabolites in urine were sulphates and glucuronides of 4-chloro-2-fluoro-5-hydroxyaniline, amounting to 5-7 and 2-3% of the administered dose, respectively. Sulphonic acid conjugates were not detected in urine, blood, kidney or liver.