The interaction of fifteen amphetamine analogs with the genetically polymorphic enzyme CYP2D6 was examined. All fourteen phenylisopropylamines tested were competitive inhibitors of CYP2D6 in human liver microsomes. The presence of a methylenedioxy group in the 3,4-positions of both amphetamine (Ki = 26.5 microM) and methamphetamine (Ki = 25 microM) increased the affinity for CYP2D6 to 1.8 and...