Evidence for involvement of non-biliary excretion into the intestines in the formation of methylsulphonyl-containing metabolites of 2-chloro-N-isopropylacetanilide (propachlor) by swine and rats

Abstract

1. Radiolabelled metabolites excreted in the urine of swine after an oral dose of ¹⁴C-propachlor were similar to those previously reported with rats and included methylsulphonyl (CH₃SO₂-)-containing metabolites.

2. A bile-duct-cannulated pig dosed orally with ¹⁴C-propachlor excreted 7.6% dose in the bile compared with approx, 75% dose with rats. Although enterohepatic circulation had been prevented with the bile-duct-cannulated pig, CH₃SO₃ metabolites of propachlor were excreted in the urine. Enterohepatic circulation had been reported to be necessary for formation of CH₃SO₂ metabolites of propachlor with rats.

3. Germ-free pigs dosed orally with ¹⁴-C-propachlor did not excrete urinary CH₃SO₂ metabolites, indicating involvement of the enteric flora in the production of these metabolites as shown previously with rats.

4. A g.l.c.-mass spectrometric specific ion monitoring technique indicated that trace amounts of CH₃SO₂ metabolites were present in the urine and bile of bile-duct-cannulated rats dosed orally with ¹⁴C-propachlor. This was confirmed by isolation and mass-spectral analyses.

5. It is concluded that after oral administration of propachlor to rats and swine, glutathione (GSH) conjugation and cysteine conjugate β-lyase activity in the enteric flora are involved in formation of CH₃SO₂ metabolites. Presumably, the GSH conjugate is formed in mammalian tissue and must be returned to the lumen of the gut to be acted upon by the gut microflora. In rats this is accomplished primarily by biliary excretion, whereas in swine a non-biliary mechanism is much more important.