Estimation of the Extent of in Vivo Formation of a Mutagenic Aromatic Amine from a Potent Thyromimetic Compound: Correlation of in Vitro and in Vivo Findings

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• 作者：Kamelia Behnia ; Georgia Cornelius ; Jian Wang ; Petia Shipkova ; Susan Johnghar ; William Washburn ; Robert Brigance ; Paul Stetsko ; Andrew Henwood ; James P. Wojciechowski ; Punit Marathe ; A. David Rodrigues ; W. Griffith Humphreys
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：June 20, 2011
• 年：2011
• 卷：24
• 期：6
• 页码：905-912
• 全文大小：841K
• 年卷期：v.24,no.6(June 20, 2011)
• ISSN：1520-5010

文摘

The development of compounds with the potential for genotoxicity poses significant safety risks as well as risks of attrition. Although genotoxicity evaluation of the parent molecule is routine and reasonably predictive, assessing the risk of commercialization when release of a genotoxic degradant and/or metabolite from a nongenotoxic parent molecule is suspected is much more challenging and resource intensive. Much of the risk of the formation of a genotoxic degradant/metabolite can be discharged with the conduct of carcinogenicity studies in models where the compound is formed, but this approach requires a great deal of time and resources. In this manuscript, we investigated the contribution of various factors (pH, serum instability, and hepatic metabolism) to the formation of a mutagenic aromatic amine from a potent and highly selective thyromimetic compound ([3-(3,5-dibromo-4-(4-hydroxy-3-isopropyl-5-methylphenoxy)-2-methylphenylamino)-3-oxopropanoic acid], compound 1), under in vitro conditions. The kinetic parameters obtained from in vitro experiments combined with the pharmacokinetics of 1in vivo (e.g., plasma concentration鈥搕ime profile and clearance) were used to estimate the extent of in vivo formation of [4-(4-amino-2,6-dibromo-3-methylphenoxy)-2-isopropyl-6-methylphenol] (compound 2), in rats upon administration of a single oral dose of 1. The agreement between the predicted values (1.9% conversion of total administered dose) with the observed levels of 2 in rats (0.2%-2.2% of the 10 mg/kg dose, 10 mg/kg) further prompted the utilization of this approach to predict the extent of release of this mutagen in humans upon administration of 1. The projection of 0.13% conversion to 2 from an efficacious daily dose of 15 mg of 1 translated to the generation of 20 渭g of 2 and provided the basis for the decision to terminate the development of 1.