Phenol elimination in the dog after intravenous injection of neoarsphenamine

Although Ehrlich himself recognized the importance of discovering the fate of salvarsan in the animal body, it was Sieburg 1 who first approached the solution of this problem. This investigator succeeded in isolating from the urine of a syphilitic patient who had received repeated intravenous injections of salvarsan the following substances: p-aminophenol, o-acetylamino phenyl hydrogen sulphate, oxycarbanil, an aminohydroxyphenylarsonic acid, C₆H₈O₄N As, and a hydroxyphenylarsonic acid, C₆H₇O₄As, besides inorganic arsenates and arsenites. He concludes that salvarsan is broken down in the system in the following way (Chart 1):

“Apparently o-aminophenol is to a comparatively small extent converted into the isomeric, highly toxic para compound, while the remainder is conjugated either with H₂SO₄ with the introduction of an acetyl group, or with urea with the subsequent elimination of 2 N H₃ radicals.”

Sieburg also studied the behavior of para-arsenobenzoic acid and of 3-amino-arsenobenzoic acid in the body of the calf and concludes that in all cases a cleavage of the toxophoric- As =AS - linking in ‘arseno’ compounds occurs in the living organism, whereby not only is the toxicity reduced, but transformation takes place into compounds which are more soluble in water and less easily soluble in other media. The characteristic effects are due to the small proportion of the substance which escapes oxidation to the arsinic acids, and to the subsequent liberation of the As₂O₃ and As₂O₅.

Sieburg's discovery of conjugated phenol derivatives resulting from the metzbolism of salvarsan as well as our independent investigations on the causes of the reactions following intravenous injections of arsphenamine and neo-arsphenamine 1 led us to direct our attention to the mechanism of detoxication which the body possesses,-the power of rendering innocuous various aromatic toxic substances by conjugation with sulphuric acid, d-glucuronic acid, urea, glycocoll, bile acids, etc.