title: 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.
abstract: 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-time 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 μg of 2 and provided the basis for the decision to terminate the development of 1.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Pennington, New Jersey 08534, United States.
authors.forename: Kamelia
authors.initials: K
authors.lastname: Behnia
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Petia
authors.initials: P
authors.lastname: Shipkova
authors.forename: Susan
authors.initials: S
authors.lastname: Johnghar
authors.forename: William
authors.initials: W
authors.lastname: Washburn
authors.forename: Robert
authors.initials: R
authors.lastname: Brigance
authors.forename: Paul
authors.initials: P
authors.lastname: Stetsko
authors.forename: Andrew
authors.initials: A
authors.lastname: Henwood
authors.forename: James P
authors.initials: JP
authors.lastname: Wojciechowski
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
mesh_terms: D000588:Amines / Q000378:metabolism / Q000633:toxicity*; D000813:Anilides / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000378:metabolism / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008954:Models, Biological; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044967:Serum / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood / Q000378:metabolism / Q000633:toxicity*
chemical_list: C561707:3-(3,5-dibromo-4-(4-hydroxy-3-isopropyl-5-methylphenoxy)-2-methylphenylamino)-3-oxopropanoic acid; D000588:Amines; D000813:Anilides; D006841:Hydrocarbons, Aromatic; D008314:Malonates; D009153:Mutagens; D013963:Thyroid Hormones