IN-VITRO METABOLISM OF ,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 antipso riatic drug 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzol[b] [1,8]naph thyridin-5 (7H)-one, was determined in vitro. Rat, dog, cynomolgus mon key, and human liver slices hydroxylated the aliphatic, cyclohexenyl r ing of the drug and conjugated the resulting carbinol. The identified metabolites comprised the corresponding 6-, 7-, and 9-carbinols, the g lucuronide of the 6-carbinol, End 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 liv er, 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 di astereomeric atropisomers. Its structure was established by C-13 and H -1 NMR spectroscopy, mass spectrometry, and comparison to an authentic sample. (C) 1998 John Wiley & Sons, Ltd.