The anticonvulsant carbamazepine 1is associatedwithadverse drug reactions (ADRs), including hepatotoxicity; oxidativemetabolism of 1has been implicated in the pathogenesisof the ADRs. We report the synthesis and evaluation of 2-monohaloand 2,8-dihalo analogues of 1that were intended to minimizereactive metabolite formation via arene oxidation and 10,11-epoxidation.Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzylderivatives. In rat hepatocytes, none of the analogues underwent oxidativedehalogenation or glutathione adduction. Some formation of the 10,11-epoxidestill occurred, but aromatic hydroxylation was not seen with the exceptionof 2-fluoro, which allowed minor monohydroxylation. Complete inhibitionof aromatic hydroxylation required at least monochlorination or difluorinationof 1. In human liver microsomes, difluoro analogue 5bunderwent 10,11-epoxidation but gave no arene oxidation. [ABSTRACT FROM AUTHOR]