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

The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10‐(3‐chlorophenyl)‐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 co...

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Published in:Biopharmaceutics & drug disposition 1998-07, Vol.19 (5), p.315-332
Main Authors: Zbaida, Shmuel, Du, Yancy, Shannon, Daniel, Laudicina, Donald, Thonoor, C. Mohan, Ng, Kwokei, Blumenkrantz, Neil, Patrick, James E., Cayen, Mitchell N., Friary, Richard, Seidl, Vera, Chan, Tze-Ming, Pramanik, Birendra, Spangler, Michael, McPhail, Andrew T.
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics
antipsoriatic drug
Biological and medical sciences
Child, Preschool
Dogs
Humans
Hydroxylation
in vitro metabolism
In Vitro Techniques
Liver - metabolism
liver slices
Macaca fascicularis
Male
Medical sciences
Naphthyridines - pharmacokinetics
Pharmacology. Drug treatments
Psoriasis - drug therapy
Rats
Rats, Sprague-Dawley
SCH 40120
Skin, nail, hair, dermoskeleton
Species Specificity
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Summary:The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10‐(3‐chlorophenyl)‐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 13C and 1H NMR spectroscopy, mass spectrometry, and comparison to an authentic sample. © 1998 John Wiley & Sons, Ltd.
ISSN:0142-2782
1099-081X
DOI:10.1002/(SICI)1099-081X(199807)19:5<315::AID-BDD107>3.0.CO;2-N