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
Corresponding Author
Shmuel Zbaida
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USASearch for more papers by this authorYancy Du
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorDaniel Shannon
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorDonald Laudicina
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorC. Mohan Thonoor
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorKwokei Ng
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorNeil Blumenkrantz
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorJames E. Patrick
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorMitchell N. Cayen
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorRichard Friary
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorVera Seidl
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorTze-Ming Chan
Department of Physical Analytical Chemical Research and Development, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorBirendra Pramanik
Department of Physical Analytical Chemical Research and Development, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorMichael Spangler
Department of Physical Analytical Chemical Research and Development, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorAndrew T. McPhail
Department of Chemistry, Paul M. Gross Chemical Laboratory, Duke University, Durham, NC 27706, USA
Search for more papers by this authorCorresponding Author
Shmuel Zbaida
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USASearch for more papers by this authorYancy Du
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorDaniel Shannon
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorDonald Laudicina
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorC. Mohan Thonoor
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorKwokei Ng
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorNeil Blumenkrantz
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorJames E. Patrick
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorMitchell N. Cayen
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop: K-15-3, 3700, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorRichard Friary
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorVera Seidl
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorTze-Ming Chan
Department of Physical Analytical Chemical Research and Development, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorBirendra Pramanik
Department of Physical Analytical Chemical Research and Development, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorMichael Spangler
Department of Physical Analytical Chemical Research and Development, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Search for more papers by this authorAndrew T. McPhail
Department of Chemistry, Paul M. Gross Chemical Laboratory, Duke University, Durham, NC 27706, USA
Search for more papers by this authorAbstract
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.
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