Metabolism of a Thyroxine Analogue, 3,5-Diiodo-4-(4′-acetoxy-3′-iodophenoxy)benzoic Acid in Rats

Abstract

1. The metabolic fate of 3,5-diiodo-4-(4′-acetoxy-3′-[¹²⁵I]iodophenoxy)-benzoic acid was studied in rats and its principal metabolites identified.

2. The drug, orally administered, was rapidly and almost quantitatively absorbed from the intestine, and was distributed to liver and kidney. Blood levels of radioactivity reached a plateau 3 to 5 h after administration, and gradually decreased. Radioactivity was rapidly excreted, largely in the bile, and entered into entero-hepatic circulation. Subsequent excretion in faeces and urine, amounted to 60 and 25%, respectively, within 72 h.

3. Repeated oral administration of the drug did not show any accumulation, except in the thyroid gland, which showed a concentration five times higher than that after a single administration.

4. The metabolic fate of the drug in animals receiving a subtoxic dose of the unlabelled drug for 4 weeks did not significantly differ from that in control animals.

5. The faecal metabolite was identified as the deacetylated drug. Glucuronide and sulphate conjugates of the deacetylated drug accounted for 48 and 30%, respectively, of the biliary metabolites. The urinary metabolite was largely iodide (80%).

6. These results indicate that the drug is eliminated by two distinct pathways of metabolism, the major one is the biliary route following deacetylation and conjugation, and the minor one is the urinary route after de-iodination.