TY - JOUR T1 - Oxidative <em>ipso</em> Substitution of 2,4-Difluoro-benzylphthalazines: Identification of a Rare Stable Quinone Methide and Subsequent GSH Conjugate JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2074 LP - 2080 DO - 10.1124/dmd.112.046268 VL - 40 IS - 11 AU - Mithat Gunduz AU - Upendra A. Argikar AU - Amin Kamel AU - Kevin Colizza AU - Jennifer L. Bushee AU - Amanda Cirello AU - Franco Lombardo AU - Shawn Harriman Y1 - 2012/11/01 UR - http://dmd.aspetjournals.org/content/40/11/2074.abstract N2 - In vitro metabolite identification and GSH trapping studies in human liver microsomes were conducted to understand the bioactivation potential of compound 1 [2-(6-(4-(4-(2,4-difluorobenzyl)phthalazin-1-yl)piperazin-1-yl)pyridin-3-yl)propan-2-ol], an inhibitor of the Hedgehog pathway. The results revealed the formation of a unique, stable quinone methide metabolite (M1) via ipso substitution of a fluorine atom and subsequent formation of a GSH adduct (M2). The stability of this metabolite arises from extensive resonance-stabilized conjugation of the substituted benzylphthalazine moiety. Cytochrome P450 (P450) phenotyping studies revealed that the formation of M1 and M2 were NADPH-dependent and primarily catalyzed by CYP3A4 among the studied P450 isoforms. In summary, an unusual and stable quinone methide metabolite of compound 1 was identified, and a mechanism was proposed for its formation via an oxidative ipso substitution. ER -