Metabolic fate of noscapine. III. Further studies on identification and determination of the metabolites.

1. From the urine of rats, rabbits and humans treated with noscapine, two novel metabolites were isolated and identified as 7-hydroxy-6-methoxyphthalide (MA-1) and 6-hydroxy-7-methoxyphthalide (MA-2), mainly by mass spectrometry. 2. MA-2 (free and conjugated) amounted to 8.5% dose in rats (n=2) and 1.7% dose in rabbits (n=2) during the first 48 h. In humans, MA-2 was excreted in amounts of 6.0 to 10.3% dose in the first 24 h urine (three men and a woman), although one woman excreted 52.5% dose as MA-2 during the same period. In all three species MA-2 was excreted 10 times more as conjugates than as the free metabolite. MA-1 was excreted only in trace amounts in the urines of three species. 3. In rabbits, the drug was metabolized also to 1-alpha-methyl-8-methoxy-6,7-dihydroxy-1-(6,7-dimethoxy-3-phthalidyl)-1,2,3,4-tetrahydroisoquinoline (4.6% dose, conjugated only) using g.l.c.-mass spectrometry. This metabolite was excreted conjugated at 0.6 to 5.2% dose in five human subjects, but was not detected in rats. 4. Three 0-demethylated metabolites of noscapine, previously reported, were determined using g.l.c.-mass spectrometry. The total demethylated metabolites (free and conjugated) amounted to 0.2%, 4.0% and 0.1-1.5% dose, respectively, in rats, rabbits and humans (n=5) in the first 24 h urine.