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Thalidomide has been shown to be metabolized mainly to phthaloylisoglutamine and a fluorescent metabolite which is probably a derivative of 3-hydroxyphthalic acid. These metabolites have been found in human, rabbit and rat urine after dosing with thalidomide. Little of the drug is excreted unchanged. Phthaloylisoglutamine has been isolated from rabbit urine and characterized. This metabolite (400 mg/kg) has no depressant effect in rats. The brain and plasma of rats killed 30 min after thalidomide administration contained thalidomide but no metabolites. The sedative effect thus appears to be due to the drug itself and not phthaloylisoglutamine. This work was supported by a grant from the Distillers Company (Biochemicals) Limited.

Triacetic acid lactone (TAL) labeled with C 14 in three carbon atoms has been synthesized. The C 14 of small oral doses of C 14 -TAL fed to rats (250–350 mg/kg) and rabbits (50–60 mg/kg) was mostly excreted in the expired air and urine within 24 hours. In 3 days, rats excreted 45–50% in the respiratory CO 2 , 20% in the urine, and 7% in the feces; 10–20% remained in the tissues. Rabbits, in about the same period, excreted 50–60% as CO 2 , 30% in the urine, and 4% in the feces; 10–20% remained in the tissues. With both rats and rabbits most of the radioactivity in the urine occurs as unchanged TAL (13–25% of dose) together with small amount of urea (2–11% of dose). In the urines of rabbits only, a third unidentified metabolite accounting for 10% of the dose, and probably a degradation product of TAL, was detected. Paper chromatography did not reveal the presence of DHA, hydroxy-DHA, or compound X in the urines of rats or rabbits dosed with C 14 -TAL. C 14 -TAL is more rapidly oxidized to CO 2 by rat kidney slices than by liver slices. DHA, hydroxy-DHA, and compound X were not detected as in vitro metabolites of TAL. Unlike DHA, TAL does not appear to combine with tissue proteins.

Publisher Summary This chapter focuses on the history of the discovery of the conjugation mechanisms. The majority of the biochemical reactions called conjugations were discovered during the 19th century, largely through the study of the composition of normal and pathological urines. Conjugates are the end products of the metabolism of many natural and foreign chemicals, and it seems logical in view of the methods then used that they should have been found before the oxidation, reduction, and hydrolysis products of foreign compounds that are usually intermediates in the formation of conjugates. The terms conjugated, conjugation, and conjugate have arisen from the use of the German word gepaart to describe the indigo-forming substances in urine. At the present time, two variants of this word are used, namely, detoxication and detoxification with possibly a shade of difference in meaning, the former being the process of reducing toxicity and the latter the capacity for reducing toxicity. Nearly all the enzyme systems involved in conjugation reactions have natural substrates, and all the conjugating agents have roles in normal intermediary metabolism apart from those involving foreign compounds. The major conjugation reactions are relatively few in number, and the conjugating agents are derived mainly from the animal's carbohydrate and amino acid sources.