Role of iodine in the toxicity of diiodomethyl-p-tolylsulfone (DIMPTS) in rats: ADME

Abstract

Metabolism of diiodomethyl-p-tolylsulfone (DIMPTS) was investigated in rats to determine the role of iodide in its toxicity. Fischer 344 (F-344) (5 or 50mg/kg) or Sprague Dawley (SD) (5mg/kg) rats were gavaged with 14C-DIMPTS or dermally applied with 5mg/kg (F-344 only) and absorption, distribution, metabolism and excretion (ADME) determined. Additional experiments were conducted with its deiodinated analog (methyl-p-tolylsulfone, MPTS) in female F-344 rats (20mg/kg) for comparison. Orally administered 14C-DIMPTS was rapidly absorbed and eliminated in urine (92%). The elimination t½ was 1–4h. Dermally applied 14C-DIMPTS remained undetectable in plasma with bioavailability ∼7%, only 5–7% of the dose was recovered in urine. DIMPTS liberated one or both of its iodine atoms upon absorption. The rate of elimination of the liberated iodide from the systemic circulation was 2- to 3-fold slower in SD than F-344 rats, which resulted in higher bioavailability of iodide to SD rats. DIMPTS was primarily oxidized at the benzylic methyl moiety forming the corresponding benzoic acid. Glutathione conjugation on the sulfonyl methyl group, via displacement of I− was also observed. Overall 67–80% of the total iodine atoms were metabolically released from DIMPTS. The MPTS was rapidly absorbed from the GI tract, metabolized and eliminated in urine similar to that of DIMPTS. These data were compared to iodide toxicokinetic results of a reproductive toxicity study for DIMPTS (80mg/kg/day) and MPTS (32mg/kg/day), where DIMPTS was toxic to dams and pups, while MPTS caused no toxicity. These data show that the liberated iodide is the ultimate toxicant of DIMPTS, which is readily transported to pups through milk, while the methyltolylsulfone backbone structure (MPTS) of DIMPTS is relatively nontoxic.