Isosalsolinol formation: a secondary reaction in the Pictet‐Spengler condensation

Plasma concentrations of compound I were measured by a modification of the radioisotope derivative technique described by Hammer & Brodie (1967). The biological half-life was 18.1 f 1-0 h as estimated by exponential regression analysis of the mean plasma levels observed from 4 to 31 h. That of amantadine was 9 to 15 h, based on urinary excretion data (Bleidner, Harmon & others, 1965). Urinary concentrations of unchanged compound I and two metabolites (structure 11, isomers a, b) were assayed by g.1.c. using a flame ionization detector, after chloroform extraction of the urine at pH 9 before and after acid hydrolysis. Compound I, unlike amantadine, was metabolized in man by mono-hydroxylation of the adamantane nucleus followed by conjugation (Chatfield & Green, unpublished observations). After a single oral dose (100 mg) of compound I to five subjects the mean 48 h urinary excretion of unchanged I and its metabolites accounted for 33.3% (range 16-0-53-9 %) of the dose. Less than 1 % of the unchanged compound was excreted, most of the urinary material being present in two isomers of the hydroxylated product 11, a and b, corresponding to different but as yet unknown positions of hydroxylation on the adamantane nucleus. The major urinary metabolite, considered as compound IIa, accounted for 30.5 % (range 15-2-48.7% of the dose, only small amounts (1-9 %, range 0*3-4.3%) of the isomer IIb being recovered. About half the total amounts of metabolites IIa and IIb were excreted as acid-labile conjugates. COMMUNICATIONS, J. Pharm. Pharmac., 1974, 26, 476