Der Metabolismus des Retinoids Ro 10‐9359. Isolierung und Identifizierung der Hauptmetaboliten aus Plasma, Urin und Faeces des Menschen sowie aus der Galle der Ratte Synthese von drei Urinmetaboliten

Abstract

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.

Pharmacokinetics of 14C‐etretinate in healthy volunteers and two patients with biliary t‐tube drainage

“…This was accomplished by maintaining the subjects in rooms (including bathrooms) equipped with yellow lights and by keeping all collection vessels and tubing wrapped or covered with aluminum foil. Ten millitres of heparinized whole blood were drawn at 112, 1,2,3,4,6,8,12,24,36,48,72,96, and 120 h and at 24-h intervals thereafter for 2 weeks. No blood samples were collected beyond 2 weeks.…”

Synthesis of Urinary Metabolites of Retinoic Acid

“…EtOH), and decarboxylated to afford 1 (51% from 8). Metabolite 1 was also prepared from 4 [6] by reaction with 3,3-ethylendioxypropylmagnesium bromide (9) affording 3- methyl-1 -[2,6,6-trimethyl-3-(tetrahydro-2 H-pyran-2-y1)-oxy-1 -cyclohexen-1 -yl]-6,6-ethylenedioxy-l -hexen-3-01 (10) (77%), which was deprotected (TsOH, aq. THF) and oxidized (Cr03/pyridine complex) to give 1 (45% from 10).…”