Sumnzavy. After the intraperitoneal administration of high doses of 14C-and 3H-labelled retinoic acid (1) to rats three major urinary metabolites have been isolated in microgram amounts by use of column, thin-layer and high-pressure liquid chromatography. Their structures were elucidated by mass spectroscopy and Fourier transform 1H-NMR. spectroscopy as 2 (S-methyl-5-[2-(2,6,6-trimethyl-3-oxo-l-cyclohcxcn-l-~l)vinyl]-2-tetrahydrofurano1ie), 3 (5-[2-(6-hydroxymethyl-2,6-dimcthyl-3-oxo-l-cyclohcxen-l-yl)vinyl]-5-methyl-2-tetrah~-drofuranone) and 4 (6-(6-hydroxymethyl-2,6-dimethyl-3-oxo-l-cyclohexen-l-yl)-4-methyl-4-hexenoic acid). In thcse metabolites the tctraene side chain of 1 is shortened and the cyclohexene ring oxidized. The radioactivity of 2 and 3 accounted for about 10% (0.9% of the dose) each, metabolite 4 for about 6 % (0.5% of the dose) of the total urinary radioactivity.

Following the intraperitoneal administration of high doses of 14C‐ and 3H‐ labelled retinoic acid (1) to rats, three major metabolites and the intact compound were isolated from the feces in microgram amounts by use of column, thin‐layer and high‐pressure liquid chromatography. Their structures were elucidated by mass spectrometry and Fourier Transform 1H‐NMR. spectroscopy as 2 (all‐trans‐4‐oxoretinoic acid), 3 (7‐trans‐9‐cis‐11‐trans‐13‐trans‐5′‐hydroxy‐retinoic acid). Hydroxylation of the 5‐methyl group of the cyclohexene ring, oxidation of the cyclohexene ring in position 4 and cis‐trans isomerisation of the nonatetraenoic acid side chain were the reactions, which produced these products from retinoic acid. The metabolites 2 and 4 each accounted for about 4% of the radioactivity administered. The metabolite 3 and the parent compound accounted for about 16% and 17% of the dose, respectively.

The Metabolism of the Retinoid Ro 10‐9359. Isolation and Identification of the Major Metabolites in Human Plasma, Urine and Feces Synthesis of Three Urinary Metabolites After oral administration of therapeutic doses of the 3H‐labelled aromatic retinoic acid analog (retinoid) Ro 10‐9359 (ethyl all‐trans‐9‐(4‐methoxy‐2,3,6‐trimethyl‐phenyl)‐3,7‐dimethyl‐2,4,6,8‐nonatetraenoate) to humans 75 and 15% of the 3H‐dose were excreted within the first five days in the feces and the urine, respectively. Using chromatographic procedures including high pressure liquid chromatography 18 metabolites could be isolated from human urine. Their structures were elucidated by mass spectrometry and FT–1H‐NMR. spectroscopy. In these urinary metabolites the tetraene side chain of the parent compound Ro 10‐9359 is shortened. The radioactivity of the identified urinary metabolites accounted for about 11% of the dose. Three urinary metabolites were synthesized. The main part of the radioactivity excreted within the first five days in the feces consisted of unchanged drug (60% of the dose). A smaller (amount 15% of the dose) could not be identified. The unchanged drug and a major metabolite, the corresponding acid, were found in human plasma. In an experiment with bile‐duct cannulated rats the radioactively labelled retinoid Ro 10‐9359 was injected intravenously. About 70% of the 3H‐dose was excreted in the bile, within the first 48 hours. The whole radioactivity of the rat bile consisted of polar metabolites. No unchanged drug could be found. After enzymatic hydrolysis of the bile conjugates three metabolites were isolated. The main metabolite (49% of the i.v. dose) was a conjugate of the corresponding acid of the parent drug, already found as free compound in human plasma. The other bile metabolites (9 and 7% of the i.v. dose) had an intact side chain, too. An enterohepatic recycling of the bile metabolites was observed in the rat.

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