In vitro metabolism of 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one, a topical antipsoriatic agent. Use of precision-cut rat, dog, monkey and human liver slices, and chemical synthesis of metabolites
✍ Scribed by Shmuel Zbaida; Yancy Du; Daniel Shannon; Donald Laudicina; C. Mohan Thonoor; Kwokei Ng; Neil Blumenkrantz; James E. Patrick; Mitchell N. Cayen; Richard Friary; Vera Seidl; Tze-Ming Chan; Birendra Pramanik; Michael Spangler; Andrew T. McPhail
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 405 KB
- Volume
- 19
- Category
- Article
- ISSN
- 0142-2782
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✦ Synopsis
The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10- (3chlorophenyl)-6,8,9,10-tetrahydrobenzol[b][1,8]naphthyridin-5(7H)-one, was determined in vitro. Rat, dog, cynomolgus monkey, and human liver slices hydroxylated the aliphatic, cyclohexenyl ring of the drug and conjugated the resulting carbinol. The identified metabolites comprised the corresponding 6-, 7-, and 9-carbinols, the glucuronide of the 6-carbinol, and the 6-ketone derived from the parent drug.
Although the three carbinols appeared in the liver isolates of all species studied, the relative amounts of these metabolites varied across species. With a high, non-physiological ratio of substrate to liver, the 6-carbinol and its glucuronide were the major metabolites in human and monkey, whereas the 6-ketone was a minor metabolite in dog.
Containing a stereogenic axis and center, the 6-carbinol existed as diastereomeric atropisomers. Its structure was established by 13 C and 1 H NMR spectroscopy, mass spectrometry, and comparison to an authentic sample.