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.

Published

Journal Article

The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzol[b][1,8]naphthyrid in-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.

Full Text

Duke Authors

Cited Authors

  • Zbaida, S; Du, Y; Shannon, D; Laudicina, D; Thonoor, CM; Ng, K; Blumenkrantz, N; Patrick, JE; Cayen, MN; Friary, R; Seidl, V; Chan, TM; Pramanik, B; Spangler, M; McPhail, AT

Published Date

  • July 1998

Published In

Volume / Issue

  • 19 / 5

Start / End Page

  • 315 - 332

PubMed ID

  • 9673784

Pubmed Central ID

  • 9673784

Electronic International Standard Serial Number (EISSN)

  • 1099-081X

International Standard Serial Number (ISSN)

  • 0142-2782

Digital Object Identifier (DOI)

  • 10.1002/(sici)1099-081x(199807)19:5<315::aid-bdd107>3.0.co;2-n

Language

  • eng