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

4区 · 医学

Article

作者: C. Mohan Thonoor ; Tze-Ming Chan ; James E. Patrick ; Richard Friary ; Neil Blumenkrantz ; Michael Spangler ; Kwokei Ng ; Andrew T. McPhail ; Shmuel Zbaida ; Birendra Pramanik ; Donald Laudicina ; Daniel Shannon ; Mitchell N. Cayen ; Vera Seidl ; Yancy Du

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.

1995-02-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

A specific enzyme immunoassay (EIA) with selective extraction for quantitation of a topical anti-inflammatory agent, SCH 40120, in human plasma

3区 · 医学

Article

作者: Zuguang Tian ; Virginia Reyes ; Chang-Jin Wang ; Chin-Chung Lin

SCH 40120 is a potent anti-inflammatory agent under development for the topical treatment of dermal inflammatory and allergic disorders such as atopic dermatitis, contact dermatitis and psoriasis. We have previously described a sensitive enzyme immunoassay (EIA) for SCH 40120 in unextracted human plasma to support clinical studies. However, severe cross-reaction with unknown metabolites was observed during validation using samples from rats dosed with 14C-SCH 40120. Therefore, a selective extraction procedure was developed to remove the unknown plasma metabolites of SCH 40120 prior to EIA quantitation. The modified EIA using extracted plasma was cross-validated with an LC method using plasma samples from dosed subjects (human and rat), thereby confirming the specificity of the assay. The EIA can reliably quantitate SCH 40120 in plasma samples from 100 pg ml-1 to 10 ng ml-1 with good linearity, accuracy and precision, and is suitable for pharmacokinetic studies in man.

1993-10-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

A sensitive enzyme immunoassay (EIA) for quantitation of the topical anti-inflammatory agent SCH 40120 in unextracted human plasma

3区 · 医学

Article

作者: Chin-Chung Lin ; Zuguang Tian ; Chang-Jin Wang ; Virginia Reyes ; Carl Gommoll

SCH 40120 is a potent acute anti-inflammatory agent under development for topical treatment of dermal inflammatory and allergic disorders such as atopic dermatitis, contact dermatitis and psoriasis. In order to support percutaneous absorption studies, a competitive enzyme immunoassay (EIA) was developed to determine SCH 40120 in unextracted plasma samples. SCH 38280, a carboxylated analogue of SCH 40120, was used as the hapten and conjugated with bovine thyroglobulin (Thy). The hapten-Thy conjugate was used as the immunogen to immunize rabbits for antibody production. The hapten was also coupled to horseradish peroxidase (HRP) to form SCH 38280-HRP, which was used as the tracer. The EIA can detect SCH 40120 concentrations as low as 50 pg ml-1 of plasma, and can reliably quantitate SCH 40120 in plasma samples from 100 pg ml-1 to 10 ng ml-1 with good linearity, accuracy and precision. A variety of structurally related compounds and potential metabolites did not significantly cross-react with the antibodies, except for a few analogues. The availability of this sensitive assay makes it possible to evaluate the pharmacokinetics of SCH 40120 in man.

100 项与 SCH-40120 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
炎症	临床2期	美国	Schering-Plough Corp.	-
炎症	临床2期	-	Merck Sharp & Dohme Corp.	-
皮肤疾病	临床2期	-	Merck Sharp & Dohme Corp.	-
皮肤疾病	临床2期	美国	Schering-Plough Corp.	-